Matthias Rothermundt

Review of immunological and immunopathological findings in schizophrenia.

The involvement of immunological and immunopathological mechanisms in the etiopathogenesis of schizophrenia has been a matter of research, with recently increasing effort. This article reviews the findings focusing on postmortem neuropathology, the blood-brain barrier, antibodies, acute phase proteins, immunocompetent cells, and activation markers of immunocompetent cells. Evidence for the two primarily postulated hypotheses (the infectious hypothesis and the autoimmune hypothesis) is critically discussed. On the basis of the findings, perspectives for future research are outlined aiming at a precise and consequent strategy to elucidate a potential involvement of immune mechanisms in the etiopathogenesis of schizophrenia.

Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients

In an attempt to define potential immunological dysfunctions in schizophrenia, we determined the production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-γ (IFN-γ), and soluble IL-2 receptor (sIL-2R) in a whole-blood assay after stimulation with phytohemagglutinin (PHA) as well as the serum concentrations of sIL-2R. Because CD4+CD45RO+T cells are the main producers of IFN-γ, we determined the percentage of these cells, as well as of pan T, CD4+T, and CD8+T cells, by flow cytometry. A whole-blood count was performed in addition. Two groups of patients were examined, paranoid-type and residual-type schizophrenics. The numbers of both monocytes and neutrophils, but not of lymphocytes, were increased significantly in the schizophrenic sample. The IFN-γ production of the schizophrenics as a whole group, and of the paranoid patients, was reduced significantly in comparison with the control group (p≤0.05). The residual patients produced less IFN-γ than the controls, but more than the paranoid patients. The latter differences did not reach statistical significance. The production of IL-4, which physiologically antagonizes the production of IFN-γ, was not significantly higher in the patient group. No changes in the lymphocyte subpopulations were observed. The production of IL-2 showed a trend toward reduction in paranoid patients, but not in residual schizophrenics. The serum sIL-2R levels were elevated slightly in schizophrenics when compared with controls. In order to rule out a possible effect of cortisol on cytokine production, 20 schizophrenic were compared with 20 age- and gendermatched controls. However, neither elevated cortisol levels were detected in the schizophrenic sample, nor significant intercorrelations between cortisol levels and cytokine production, or levels of sIL-2R, respectively. In summary, our data reinforce the possibility of immune dysfunction in schizophrenia and point to the possible relevance of disease subgroups in this respect.

Inflammatory markers in major depression and melancholia

BACKGROUND There is evidence that patients with major depression (MD) also suffer an inflammatory immune reaction. However, the results remain ambiguous. This could be due to the psychiatrically heterogeneous patient samples investigated in many published studies. Since melancholic depression is psychopathologically and possibly etiologically different from non-melancholic MD, we focused on investigating immune parameters in these two subgroups. METHODS 43 in-patients suffering from acute major depression were diagnosed, sub-classified according to DSM IV criteria, and compared to 43 matched healthy controls. Cell counts were determined by morphology, and acute phase proteins [c-reactive protein (CRP), alpha(2)-macroglobulin (A2M), haptoglobin (HP)] were measured by laser nephelometry. Cytokine production (IL-1beta) upon mitogen stimulation was measured by ELISA in a whole blood assay. RESULTS Non-melancholic patients showed increased monocyte counts and A2M serum concentrations in the acute stage of disease and after 2 and 4 weeks of treatment. Melancholic patients demonstrated a decreased monocyte count upon admission and after 4 weeks of treatment. HP levels and IL-1beta production were unchanged in all studied subjects. LIMITATIONS Medication of the patients varied. The differentiation between melancholic and non-melancholic depression was performed clinically and was not performed using any standardized instrument. CONCLUSION Melancholic and non-melancholic patients show different immune patterns. This differentiation might clarify immunological findings in MD and point towards etiological factors that are involved in the development of various subtypes of MD.

Different immune patterns in melancholic and non-melancholic major depression

Abstract The search for immune patterns in major depression has thus far resulted in ambiguous findings, probably because patient samples are psychiatrically heterogeneous. We therefore focused on a detailed classification of subtypes of major depression, comparing patients with melancholic and non-melancholic major depression.Inpatients suffering from acute major depression were diagnosed and subclassified according to DSM IV criteria. Cell counts were determined by FACS analysis and morphology. Cytokine production (IL-2, IFN-γ, IL-10) upon mitogen stimulation was measured by ELISA in a whole blood assay.Non-melancholic patients showed increased counts of leukocytes, lymphocytes and NK-cells in the acute stage of disease and after two and four weeks of treatment. Their lymphokine production was unchanged compared to that of healthy controls. Melancholic patients on the other hand demonstrated normal cell counts but a decreased production of IL-2, IFN-γ and IL-10 during the acute stage of disease followed by a normalization with clinical improvement.Melancholic and non-melancholic patients showed different immune patterns. Classifying melancholic and non-melancholic patients is helpful towards the identification of immune characteristics typical for these diseases.

Effects of amantadine treatment on in vitro production of interleukin-2 in de-novo patients with idiopathic Parkinson's disease.

An involvement of immunological events in the process of neurodegeneration has frequently been reported. We investigated the cytokine producing capacity for interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) in whole blood cultures of de-novo patients with idiopathic Parkinsons disease (PD) at the time of first diagnosis and after oral amantadine treatment. Before treatment, productions of IL-2 and IFN-gamma were markedly decreased in PD patients compared to patients with major depressive disorder and healthy controls. After amantadine treatment, the in vitro IL-2 secretion defect was corrected to normal levels in half of the patients, and the increase in IL-2 production was correlated with an increase in IFN-gamma secretion. Our findings suggest that immunological abnormalities occur in the course of PD and that a formerly unappreciated therapeutic potential of amantadine may arise from its immunomodulatory effects on altered T cell function in patients with PD.

The Influence of Typical and Atypical Neuroleptic Drugs in the Production of Interleukin-2 and Interferon-Gamma in vitro

Alterations of cytokine levels represent the most consistent finding from studies concerning the involvement of the immune system in the etiology of schizophrenia. These results have been discussed controversially due to the potential influence of drug treatment on cytokine production and on the experimental procedures used for cytokine measurement. In the present study, the influences of typical and atypical neuroleptic drugs (haloperidol and clozapine) as well as a tricyclic antidepressive drug (amitriptyline) on cytokine levels (IL-2 and IFN-γ) were examined in vitro in a whole blood assay under various conditions of phytohemagglutinin (PHA) stimulation and drug incubation. Stimulation was enhanced by haloperidol and clozapine, but not by the antidepressant, meaning that the results of decreased cytokine levels seen in earlier studies in schizophrenic patients cannot be explained through drug influences alone. Furthermore, our findings allow us to conclude that, in contrast to the antidepressant drug, the typical and atypical neuroleptic drugs seem to influence the examined cytokine levels.

Increased serum neopterin levels in acutely ill and recovered schizophrenic patients

Twenty-nine in-patients with acute schizophrenia were examined to assess serum neopterin levels by ELISA at two points of time: during the state of acute symptoms and after clinical recovery at the point of discharge (at an interval of 30.84 +/- 15.22 days). Patients showed significantly higher levels of neopterin than controls. Moreover, the neopterin levels were significantly higher in patients after clinical improvement than in acutely ill patients. Neopterin levels in patients after clinical recovery were negatively correlated to scores of psychopathological symptoms, and positively to neuroleptic medication at the acute stage of the disease. The increase of serum neopterin during treatment of schizophrenia may reflect an up-regulation of dopamine turnover, rather than immunological activity.

Cytokine Production in Depressed Patients

Traditionally, the nervous, endocrine, and immune systeme have been regarded as separate systems both in clinical circumstances as well as in research. A concept of an interrelationship between the immune system and the nervous system, i.e. the psychological state, has been suggested before the first studies in psychoneuroimmunology have been conducted. Several authors implicated that mood disturbances may result in an increased susceptibility to infectious or neoplastic diseases (Ader, Feiten, & Cohen, 1991; Crow 1978; King, Cooper, Earle, Martin, McFerran, Rima, & Wisdom, 1985).

Immunological research in clinical psychiatry: report on the consensus debate during the 7th Expert Meeting on Psychiatry and Immunology.

There is convincing evidence that cytokines are involved in the physiology and pathophysiology of brain function and interact with different neurotransmitter and neuroendocrine pathways. The possible involvement of the immune system in the neurobiological mechanisms that underlie psychiatric disorders has attracted increasing attention in recent years. Thus in the last decade, numerous clinical studies have demonstrated dysregulated immune functions in patients with psychiatric disorders. Such findings formed the basis of the 7th Expert Meeting on Psychiatry and Immunology in Muenster, Germany, where a consensus symposium was held to consider the strengths and weaknesses of current research in psychoneuroimmunology. Following a general overview of the field, the following topics were discussed: (1) methodological problems in laboratory procedures and recruitment of clinical samples; (2) the importance of pre-clinical research and animal models in psychiatric research; (3) the problem of statistical vs biological relevance. It was concluded that, despite a fruitful proliferation of research activities throughout the last decade, the continuous elaboration of methodological standards including the implementation of hypothesis-driven research represents a task that is likely to prove crucial for the future development of immunology research in clinical psychiatry.

Cytokines in schizophrenia. Results from a longitudinal study

Several lines of evidence indicate that an immunological dysfunction may contribute to the multifactoral etiology of schizophrenia (Kirch, 1993; Syvalahti, 1994; Wright et al., 1993). One approach to further investigate this dysfunction focuses on the field of cytokines. Cytokines are protein mediators that are produced by leukocytes. There is a complex interaction between the different immunocompetent cells, their products and mediators. Cytokines regulate the differentiation and activation of the immunologically active cells and can be regarded as functional markers of cellular immunity.