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Haloperidol does not affect the level of serum-soluble interleukin-2 receptor in drug-free male schizophrenics
... Neither short-term (13) nor long-term (14,15) haloperidol treatment affects plasma levels of soluble interleukin-2 receptor. We extended the database of our preliminary report (15) and present here the time course of rectal temperature, white blood cell counts, and plasma levels of various cytokines and soluble cytokine receptors in psychiatric patients during 6 weeks of treatment with haloperidol. ...
... DISCUSSION This study demonstrates that haloperidol treatment for 6 weeks has no effect on rectal temperature, white blood cell counts, and the plasma levels of various cytokines and soluble cytokine receptors. These findings extend reports showing that short-term (13) and longterm (14,15) haloperidol treatment does not affect the plasma level of soluble interleukin-2 receptor. Although these results do not exclude effects of haloperidol on other aspects of immunity, they allow three conclusions. ...
Clozapine increases the levels of cytokines and soluble cytokine receptors. The authors investigated whether haloperidol has similar effects.
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.
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.
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.
... CSF levels of IL-2 determined in the only study were not affected by haloperidol treatment (McAllister et al., 1995). Two groups of researchers reported no influence of haloperidol on the plasma/serum levels of sIL-2R (Kim et al., 1995;Pollmächer et al., 1997b), whereas in another ex vivo study, haloperidol enhanced LPS-stimulated production of this receptor. The effect of haloperidol was particularly evident in patients with a predominance of positive symptoms (Kowalski et al., 2000). ...
... haloperidol; CLO, clozapine; M, no effect; fl, decrease; ›, increase; ?, not investigated. References: 1 Kim et al. (2000); 2 Zhang et al. (2004); 3 McAllister et al. (1995); 4 Lu et al. (2004); 5 Kowalski et al. (2000); 6 Hinze-Selch et al. (1998); 7 Rudolf et al. (2002); 8 Szuster-Ciesielska et al. (2004); 9 Leykin et al. (1997); 10 Pollmächer et al. (1997b); 11Kim et al. (1995);12 Haack et al. (1999);13 Pollmächer et al. (1996);14 Pollmächer et al. (1995); 15Hinze-Selch et al. (1996);16 Maes et al. (1994);17 Maes et al. (1997);18 Monteleone et al. (1997);19 Kowalski et al. (2001); 20Moots et al. (1999); 21 Song et al. (2000). ...
Growing evidence suggests that the immune, endocrine, and nervous systems interact with each other through cytokines, hormones, and neurotransmitters. The activation of the cytokine systems may be involved in the neuropathological changes occurring in the central nervous system (CNS) of schizophrenic patients. Numerous studies report that treatment with antipsychotic drugs affects the cytokine network. Hence, it is plausible that the influence of antipsychotics on the cytokine systems may be responsible for their clinical efficacy in schizophrenia. This article reviews current data on the cytokine-modulating potential of antipsychotic drugs. First, basic information on the cytokine networks with special reference to their role in the CNS as well as an up-to-date knowledge of the cytokine alterations in schizophrenia is outlined. Second, the hitherto published studies on the influence of antipsychotics on the cytokine system are reviewed. Third, the possible mechanisms underlying antipsychotics' potential to influence the cytokine networks and the most relevant aspects of this activity are discussed. Finally, limitations of the presented studies and prospects of future research are delineated.
... However no alterations in this parameter were reported in anxiety disorders [Spivak et al., 1997;Rapaport and Stein , 1994a,b;Maes et al., 1994a]. Antipsychotic treatment was reported to increase sIL-2R levels [Maes et al., 1994b;Pollmacher et al., 1995Pollmacher et al., , 1996Muller et al., 1997], although not all studies could replicate this result [Kim et al., 1995;Pollmacher et al., 1997]. ...
The following manuscript is mainly conceptual in nature. It should be read with reservation since the relevance of its suggestions have yet to be proven. Basically it proposes two rules for the differentiation between primary illness-related pathophysiological vs. secondary adaptational processes. These rules may guide hypotheses generation for further research that is aimed at understanding psychiatric disorders and their shared and unshared mechanisms. For example, in the case of anxiety disorders and depression, it may be of interest to learn if their shared properties are of primary pathophysiological or secondary adaptational significance. We first present some historical observations on the development of the concept of “secondary adaptational processes.” We assume such adaptational processes are generated by the organism in order to compensate for primary pathophysiological malfunction or impairment. Next, we propose rules that may enable the dissection of secondary adaptational from primary pathophysiological processes. We also discuss the possible implications of designing studies to sort out these processes, suggesting that the understanding of adaptational processes, may explain the effects of “placebo treatment.” Finally we illustrate the application of these rules by two examples: a) amygdala activation, a biological alteration shared by anxiety disorders and major depression and b) elevated plasma soluble interleukin 2 receptor, an unshared property by anxiety disorders and major depression. Also, the first example relates to a biological perturbation associated with a primary pathophysiological mechanism, while the second represents a biological alteration associated with secondary adaptational processes. Depression and Anxiety 14:105–111, 2001. © 2001 Wiley-Liss, Inc.
... This proÞle of physiological activities is similar to that of the classical antipsychotic haloperidol, but distinct from that of the atypical antipsychotic clozapine. Similar to haloperidol (Kim et al. 1995;Pollmächer et al. 1997) and in contrast to clozapine , PAN is devoid of in vivo immunomodulatory e¤ects. Thus, the results do not support the assumption that r receptors play a role in similar physiological mechanisms in brain and immune cells (Fudenberg et al. 1984). ...
Panamesine (PAN) is a nearly specific sigma ligand. Recently, we showed that PAN in doses up to 90 mg/day improved psychometric variables in patients with an acute episode of schizophrenia. No side effects connected to the extrapyramidal motoric system occurred; there was even an absence of daytime sedation. We investigated the effects of PAN on plasma cytokine and soluble cytokine receptor levels and blood cell counts during 4 weeks in ten patients out of the previous study sample. Under PAN treatment, tumor necrosis factor (TNF)-alpha, soluble TNF receptors p55 and p75, and soluble interleukin-2 receptor levels were not increased and neither were monocyte and lymphocyte counts affected. This absence of immunomodulation is in contrast to clozapine, but similar to haloperidol treatment. In a second study, a single dose of PAN (30 mg) or placebo was administered at 2200 hours to ten young male controls in order to investigate changes in the sleep EEG under the substance. Sleep efficiency index increased, whereas time spent awake decreased. No significant changes in rapid eye movement (REM) sleep or non-REM parameters occurred. The sleep-EEG investigation showed sleep-consolidating effects of the drug, comparable to those of classical neuroleptics. Our results support the hypothesis that the sigma ligand PAN, which has antipsychotic properties, shares biological aspects with haloperidol.
Background:
Schizophrenia is a major psychiatric disorder with unknown aetiology. Recent evidence suggests a potential role for cytokines in its pathophysiology and that antipsychotic medication may alter this. While the aetiology of schizophrenia remains only partly understood, an altered immune function representing an important avenue of further discovery. In this systematic review and meta-analysis we focus on the specific effects of second generation antipsychotics risperidone and clozapine on inflammatory cytokines.
Methods:
A defined systematic search of PubMed and Web of Science databases was performed to identify relevant studies published between Jan 1900 and May 2022. After screening of 2969 papers, 43 studies (27 single-arm and 8 dual-arm) were included that consisted of a total of 1421 patients with schizophrenia in the systematic review. From these, twenty studies (4 dual-arm; 678 patients) had data available on which a meta-analysis could be carried out.
Results:
Our meta-analysis showed a significant reduction of pro-inflammatory cytokines post-risperidone treatment in the absence of a similar association with clozapine. Subgroup analyses (First episode v chronic) demonstrated that duration of illness influenced the extent of cytokine alteration; risperidone treatment produced significant cytokine changes (lowered IL-6 and TNF-α) in chronic patients but not in first-episode psychosis (FEP) patients.
Conclusion:
Varying treatment effects on cytokines can be observed by the use of different antipsychotic drugs. The cytokine alterations post-treatment are influenced by the specific antipsychotic drugs and patient status. This may explain disease progression in certain patient groups and influence therapeutic choices in the future.
Evidence supports that macrophages as well as lymphocytes and their products may be involved in the pathophysiology of psychiatric disorders. Whether patients with bipolar disorder have activation or reduction of immunity during a manic episode remains unclear.
The purpose of this case-control study was to investigate the lymphocyte proliferation to phytohemagglutinin (PHA), concanavalin A, and pokeweed mitogen, and plasma levels of soluble interleukin-2 receptor (sIL-2R) and sIL-6R in patients with bipolar mania (DSM-III-R). The subjects were 23 physically healthy patients with Young Mania Rating Scale (YMRS) scores > or = 26 as well as aged < or = 45 years and 23 age- and gender-matched normal control subjects. The above immune variables were measured in acute mania and consequent remission (YMRS scores < or = 12) among bipolar patients.
The lymphocyte proliferation to PHA and the plasma sIL-2R levels, but not sIL-6R, of bipolar patients were significantly higher in acute mania than in consequent remission. These elevations were not due to differences in medication status. Only in acute mania were the plasma sIL-2R levels of patients significantly higher than control subjects. A positive correlation between the changes of manic severity and plasma sIL-2R levels was observed. Remitted bipolar patients and normal control subjects did not differ in any of these measures.
Cell-mediated immunity activation in bipolar mania was demonstrated and may be through a specifically state-dependent immune response.
Autistic disorder, also known as early infantile autism, is a developmental disorder of unknown etiology. However, there is some evidence to suggest that abnormalities of the immune system mediate the pathophysiology of autistic disorder. Cytokines, which play a pivotal role in initiating and maintaining immune responses, have been implicated in the etiopathogenesis of major neuropsychiatric disorders including autism. Cytokines are synthesized in the periphery, as well as in the central nervous system, and exert their effects by binding to their receptors in the nervous tissues. It is suggested that, in genetically predisposed individuals, overproduction or decreased synthesis of certain cytokines may result in neurodevelopmental arrest and/or neurotoxicity.
The expanding field of psychoneuroimmunology has markedly increased knowledge about the interference of the central nervous system and the immune system. Immunological abnormalities in psychiatric patients have been repeatedly described in the last century. Modern concepts of immunology and the growing knowledge of psychoneuroimmunology may help in understanding the distinct immunological mechanisms in psychiatric disorders. One of these concepts regarding the adaptive immune system is the discrimination between Th1-like cell-mediated and Th2-like antibody-related immune responses. This article systematically describes alterations of Th1- or Th2-specific parameters in the major psychiatric disorders schizophrenia, major depression, and Alzheimer's disease. There are several hints of associations of these two distinct arms of immune response with subgroups of schizophrenia and major depression. The immunological research in Alzheimer's disease has already led to a preclinical model of immunotherapy. Categorization of immune parameters may also help to identify a possible immune-related pathophysiology in psychotic and affective disorders, resulting in specific treatment strategies.
Neuropeptides are heterogeneously distributed throughout the digestive, circulatory, and nervous systems and serve as neurotransmitters, neuromodulators, and hormones. Neuropeptides are phylogenetically conserved and have been demonstrated to regulate numerous behaviors. They have been hypothesized to be pathologically involved in several psychiatric disorders, including schizophrenia. On the basis of preclinical data, numerous studies have sought to examine the role of neuropeptide systems in schizophrenia. This chapter reviews the clinical data, linking alterations in neuropeptide systems to the etiology, pathophysiology, and treatment of schizophrenia. Data for the following neuropeptide systems are included: arginine-vasopressin, cholecystokinin (CCK), corticotropin-releasing factor (CRF), interleukins, neuregulin 1 (NRG1), neurotensin (NT), neuropeptide Y (NPY), opioids, secretin, somatostatin, tachykinins, thyrotropin-releasing hormone (TRH), and vasoactive intestinal peptide (VIP). Data from cerebrospinal fluid (CSF), postmortem and genetic studies, as well as clinical trials are described. Despite the inherent difficulties associated with human studies (including small sample size, variable duration of illness, medication status, the presence of comorbid psychiatric disorders, and diagnostic heterogeneity), several findings are noteworthy. Postmortem studies support disease-related alterations in several neuropeptide systems in the frontal and temporal cortices. The strongest genetic evidence supporting a role for neuropeptides in schizophrenia are those studies linking polymorphisms in NRG1 and the CCKA receptor with schizophrenia. Finally, the only compounds that act directly on neuropeptide systems that have demonstrated therapeutic efficacy in schizophrenia are neurokinin receptor antagonists. Clearly, additional investigation into the role of neuropeptide systems in the etiology, pathophysiology, and treatment of schizophrenia is warranted.
Neurochemical investigation has played a major role in the search for the cause of schizophrenia. Initial research strategies involved the direct measurement of neurochemical substances in biological fluids. Subsequently, indirect measures of brain biochemistry including pituitary hormones and responses to pharmacologic probes were examined. Recent advances in in vivo functional neuroimaging, biochemical neuropathology, and molecular genetics have extended the scope of clinical neurochemical studies. The historical emphasis on the dopamine neurotransmitter system has subsided in the wake of the demonstrated limitations of the dopamine hypothesis of schizophrenia and increased evidence for the role of other neurotransmitters in the pathophysiology of schizophrenia as well as their interactions with dopamine neural systems. The neurotransmitters that have come under increasing scrutiny include serotonin, norepinephrine, glutamate, and related excitatory amino acids, and the neuropeptides cholecystokinin and neurotensin. In this article, the authors reviewed significant recently published neurochemical and neuroendocrine studies of schizophrenia in the context of previous work and found an extensive but fragmentary body of data which provides neither consistent nor conclusive evidence for any specific etiologic theory. Aspects of the disease and methodological limitations that may account for this as well as future research strategies are discussed.
A bidirectional flow of information exists between the CNS and the neuroendocrine and immune systems, representing an important homeostatic mechanism in the body. Lymphokines and other products of immunocompetent cells seem to play a crucial role in this communication and seem to exert powerful effects on neurones in the brain. In this article, Giuseppe Nisticò and Giovambattista De Sarro describe the central effects following interleukin 2 (IL-2) microinfusion into several areas of the rat brain. The locus coeruleus seems to be the main site in the brain through which IL-2 exerts soporific effects. In addition, the possible transducing mechanisms coupling IL-2 receptor stimulation and the electroencephalogram (EEG) spectrum power responses elicited from the locus coeruleus seem to involve stimulation of specific receptors coupled to adenylate cyclase through a Gi protein.
Investigated whether serum soluble interleukin-2 receptors (IL-2R) elevations previously found in medicated schizophrenics may represent a neuroleptic artifact by studying the acute effects of haloperidol on serum soluble IL-2Rs from 28 healthy male Ss. Haloperidol did not acutely alter serum soluble IL-2Rs levels in these Ss. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This study was designed to determine the effect of the phenothiazine chlorpromazine (CPZ) on the activation of human thymocytes. We provide evidence that CPZ inhibits the accumulation of mRNA specific for the lymphokines, interleukin 2, interferon-gamma, tumor necrosis factor alpha and the proto-oncogene c-myc; by contrast, the accumulation of mRNA specific for the alpha chain of the interleukin 2 receptor and the subsequent early expression of Tac antigen on the cell surface is not inhibited by CPZ. The inhibition of the expression of lymphokine-specific mRNA results in a decrease in interferon-gamma synthesis and in inhibition of thymocyte proliferation as determined by the incorporation of [3H]thymidine. In addition, we show that activation of protein kinase C (PKC) in human thymocytes by 12-O-tetradecanoyl phorbol 13-acetate (TPA) causes the phosphorylation of a protein of a molecular mass of approximately 75 kDa. The function of this protein is as yet not defined, but it is possible that it plays a role in the transduction of the signals to the nucleus which in turn elicit the expression of the genes coding for c-myc and for the lymphokines required for thymocyte activation. We also demonstrate that CPZ, like the immunosuppressant drug cyclosporin A does not inhibit the phosphorylation of the 75-kDa protein which is induced by the activation of PKC by TPA and does not affect phosphoinositide breakdown, indicating that it exerts its effect at a site distal to the activation of PKC. These observations demonstrate that CPZ has an immunoregulatory function in addition to its psychotropic activity.
Recent studies have identified immunologic abnormalities in some schizophrenic subjects. This experiment replicates previous findings that serum soluble interleukin-2 receptors (SIL-2Rs) are elevated in schizophrenic patients, and is the first study to describe this phenomenon in non-Caucasian patients. Despite differences between Korean and Caucasian schizophrenic patients in absolute serum SIL-2R levels, both groups were significantly elevated when compared with their respective ethnic control groups (477 +/- 171 U/ml versus 354 +/- 172 U/ml and 763 +/- 347 U/ml versus 567 +/- 231 U/ml, respectively). Neither age, gender, medication status, nor duration of illness correlated with SIL-2R levels. These findings are further evidence that immune activation is present, regardless of ethnic origin, in some schizophrenic patients.
The pathophysiology of psychotic and other symptoms in schizophrenia remains a mystery despite decades of research. Even though it has been suspected for many years that autoimmune mechanisms may play a role in the pathophysiology of schizophrenia, firm evidence for this hypothesis has been lacking. Our studies, over the last 10 years, have revealed that a subgroup of schizophrenics have several significant immunological abnormalities, including increased prevalence of autoimmune diseases and of antinuclear antibodies (ANA) and anticytoplasmic antibodies (ACA), decreased lymphocyte interleukin-2 (IL-2) production, increased serum IL-2 receptor concentration, increased serum IL-6 concentration, and an association with HLA antigens. These findings are characteristic of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis and insulin-dependent diabetes mellitus. We also found that some schizophrenics have antibodies to hippocampal antigens (AHA) in their serum, together with lowered IL-2 production. None of the above findings can be interpreted as definitely confirming the role of autoimmunity in schizophrenia. Nevertheless, taken together, the recent evidence points towards the existence of a subgroup of schizophrenics who have immunological findings consistent with that hypothesis. Further studies directed at finding the brain antigens targeted by the immune system in these patients, and longitudinal studies correlating clinical and immune changes over time, are needed.
The influence of recombinant bovine prolactin (PRL) and recombinant bovine growth hormone (GH) was examined on the popliteal lymph node (PLN) expression of interleukin-2 receptors (IL-2R) in female Snell dwarf mice and normal litter mates after concanavalin A footpad injection. The absolute number of PLN CD4+, CD8+, or B+ cells of dwarf mice was less than that observed for normal litter mates, but when adjusted for the difference in body weight, only the absolute number of B cells was lower in dwarf animals when compared with normal litter mates. The injection of PRL or GH did not alter the observation. The administration of recombinant bovine PRL to normal animals, but not recombinant bovine GH, increased the expression of IL-2R or unstimulated PLN CD4+ and CD8+ subsets. Hormone administration to dwarf animals, however, did not alter the expression of IL-2R on unstimulated PLN T cell subsets. PLN cells from dwarf animals were poorly activated in vivo after injection of concanavalin A and the level of IL-2R expression induced was only 50% of that seen in the PLN of normal animals. The administration of PRL and GH completely corrected the defective induction of IL-2R expression on PLN from dwarf animals after concanavalin A stimulation. These findings strongly suggest that PRL and/or GH play an important role at some stage of the T cell activation process in vivo. Further studies are needed to precisely identify the defect in the dwarf mice.
Neurochemistry and neuroen-docrinology of schizophrenia: A selective review
- Ja Lieberman
- Koreen
- Ar
Lieberman JA, Koreen AR (1993): Neurochemistry and neuroen-docrinology of schizophrenia: A selective review. Schizophr Bull 19:371-429.