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27. Antiinflammatory therapy in psychiatric disorders
S16
Abstracts / Brain, Behavior, and Immunity 23 (2009) S8–S23
Introduction: Characterization of T-cell subsets has been used for diagnoses in autoimmune diseases. In psychiatric disorders, there is evidence for low level inflammatory process in the CNS. Here we compared lymphocyte cell surface markers measured by multicolor flow cytometry (BD FACSAriaTM) in patients with psychiatric (MPD) and neurological diseases in paired samples of CSF and blood (PB). Methods and CSF and PBMC were collected simultaneously from 45 patients, 17 MPD patients, 16 with non-inflammatory neurological diseases (NIND), 7 with meningitis and 5 with chronic inflammatory diseases (CIND). Samples were stained after separation with monoclonal antibodies directed against CD4, CD8, CD25, CD45, CD69, CD127 (BD and Caltag-Invitrogen) and were analyzed by BD FACSAriaTM cytometer and BD FACSDiva software. Significant differences (p < 0.05) were observed in PB for CD4+ cells (meningitis: 45.8% versus NIND: 33.06%/ CIND: 31.03%); in PB for CD4+CD45RO+ cells (meningitis: 24.08% versus CIND:11.12%); in PB for the low frequency subpopulation CD4+CD25+ (meningitis:0.89% versus CIND: 0.28%/ MPD: 0.39%); and in CSF for CD4+CD127dim cells (meningitis: 5.15% versus MPD: 10.18%). A significantly higher frequency of CD4+CD25+CD127dim, representing Tregs were observed in PB of meningitis (0.25%) versus CIND (0.09%). Cluster analysis revealed 6 out of 17 MPD displaying a ratio of CD4+/CD8+ cells in PB > 3.2, but only 2 NIND patients. In conclusion, we applied flow cytometry to define lymphocyte subsets through activation markers and Tregs in the CSF and paired peripheral blood in patients diagnosed with neurological and psychiatric disorders. We observed trends and significant differences in the distribution and frequencies in the two investigated compartments, CSF and peripheral blood, indicating different aberrations of immune function in the diseases and in the compartments. doi:10.1016/j.bbi.2009.05.029
27. Antiinflammatory therapy in psychiatric disorders Norbert Müller, Markus Schwarz Department of Psychiatry and Psychotherapy, University of Munich, LMU Munich, Germany A persistent (chronic) infection as aetiological factor in schizophrenia is discussed since many years. Signs of inflammation were observed in schizophrenic brains. Results of epidemiological studies showed that infection of the CNS in childhood increases the risk of becoming psychotic later on fivefold. Recent research points out that not one single pathogen but the immune response of the mother is related to the increased risk for schizophrenia. Several reports described increased serum IL-6 levels in schizophrenia. IL-6 is a product of activated monocytes and of the activation of the type-2 immune response. Moreover, several other signs of activation of the type-2 immune response are described in schizophrenia, while the type-1 immune response is decreased in the majority of schizophrenic patients. Mechanisms involved in the inflammatory process in schizophrenia will be outlined. Proinflammatory cytokines, such as IL-6, IL-1 and TNF appear to be elevated at least in the peripheral blood of depressed patients. Thus IDO activity may be enhanced in depressed patients through these cytokines. Although IL-6 does not directly act on IDO, its elevated levels in serum may contribute to IDO activation within the CNS by the stimulatory effect on PGE2, which acts as cofactor in the activation of IDO. This fits with a report on the correlation of increased in vitro IL-6 production with decreased tryptophan levels in depressed. Due to the increase of proinflammatory cytokines and PGE2 in some psychiatric patients, antiinflammatory treatment would be expected to show advantagous effects in schizophrenic and depressed patients. Possible therapeutic
strategies based on immune-modulatory effects including cyclooxygenase-2 inhibition will be discussed. doi:10.1016/j.bbi.2009.05.030
28. Changes in prolactin levels as predictor of response to treatment with aripiprazole Richard Musil, Michael Riedel, Ilja Spellmann, Markus Opgen-Rhein, Markus J. Schwarz Department of Psychiatry and Psychotherapy, University of Munich, LMU Munich, Germany Aripiprazole is a partial agonist at D2 receptors and has been shown to normalize antipsychotic-induced elevated prolactin levels. Changes in prolactin levels have previously been shown to correlate with symptom reduction in patients treated with typical anti-psychotics. In this study we were interested to see whether aripiprazole serum levels, doses or prolactin changes correlate with treatment response in schizophrenic patients. This was an open label eightweek trial evaluating 50 patients with DSM-IV diagnosis of schizophrenia. The patients were treated mono-therapeutically with aripiprazole. Efficacy was assessed weekly using the Positive and Negative Syndrome Scale (PANSS). Serum concentrations of aripiprazole and dehydro-aripiprazole were measured with HPLC and prolactin levels with ELECSYS (Roche Diagnostics). Aripiprazole showed significant improvement in PANSS total and all sub-scores between baseline and endpoint visit. Response to therapy did not correlate with dose (ANOVA: p = 0.953) or serum concentrations (aripiprazole: r = 0.002; dehydro-aripiprazole: r = 0.123). Prolactin levels decreased highly significant already within the first week of treatment with aripiprazole (T = 3.968; p < 0.001). Interestingly we found a differentiated and distinctive correlation between the reduction in prolactin levels within the first week of treatment and clinical improvement in PANSS global (r = 0.723; p = 0.002) and negative scores (r = 0.696; p = 0.003). Negative symptoms in schizophrenia were proposed to originate in increased dopamine efflux in the prefrontal cortex. The partial antagonistic effect of aripiprazole was hypothesized to normalize dopamine levels. The same mechanism might account for the inhibitory effect on prolactin secretion in the pituitary. Thus our results suggest a parallel antagonistic effect in different cortical regions. In this context prolactin might function as a predictor for therapy response to aripiprazole in the course of treatment. doi:10.1016/j.bbi.2009.05.031
29. Suppression of IL-6 production from cholinergic stimulated PBMS is connected to high expression of non-a-Bungarotoxin nicotine type of acetylcholine receptor on CD14+ cells A. Nast a, O. Malysheva b, A. Krause c, M. Wahle d, CGO. Baerwald b a Medizinische Department of Internal Medicine, Rheumatology and Clinical Immunology, Charité—University Hospital, Berlin, Germany b Department of Internal Medicine II, University Hospital Leipzig, Leipzig, Germany c Immanuel Hospital, Rheumatology Clinic, Berlin, Germany d Klinikum der Johann W. Goethe-Universität Frankfurt, Medical Clinic II, Frankfurt, Germany
Introduction: Increasing evidence indicates that PBMC possess a cholinergic system, consisting of different subtypes of cholinergic
Abstracts / Brain, Behavior, and Immunity 23 (2009) S8–S23
Introduction: Characterization of T-cell subsets has been used for diagnoses in autoimmune diseases. In psychiatric disorders, there is evidence for low level inflammatory process in the CNS. Here we compared lymphocyte cell surface markers measured by multicolor flow cytometry (BD FACSAriaTM) in patients with psychiatric (MPD) and neurological diseases in paired samples of CSF and blood (PB). Methods and CSF and PBMC were collected simultaneously from 45 patients, 17 MPD patients, 16 with non-inflammatory neurological diseases (NIND), 7 with meningitis and 5 with chronic inflammatory diseases (CIND). Samples were stained after separation with monoclonal antibodies directed against CD4, CD8, CD25, CD45, CD69, CD127 (BD and Caltag-Invitrogen) and were analyzed by BD FACSAriaTM cytometer and BD FACSDiva software. Significant differences (p < 0.05) were observed in PB for CD4+ cells (meningitis: 45.8% versus NIND: 33.06%/ CIND: 31.03%); in PB for CD4+CD45RO+ cells (meningitis: 24.08% versus CIND:11.12%); in PB for the low frequency subpopulation CD4+CD25+ (meningitis:0.89% versus CIND: 0.28%/ MPD: 0.39%); and in CSF for CD4+CD127dim cells (meningitis: 5.15% versus MPD: 10.18%). A significantly higher frequency of CD4+CD25+CD127dim, representing Tregs were observed in PB of meningitis (0.25%) versus CIND (0.09%). Cluster analysis revealed 6 out of 17 MPD displaying a ratio of CD4+/CD8+ cells in PB > 3.2, but only 2 NIND patients. In conclusion, we applied flow cytometry to define lymphocyte subsets through activation markers and Tregs in the CSF and paired peripheral blood in patients diagnosed with neurological and psychiatric disorders. We observed trends and significant differences in the distribution and frequencies in the two investigated compartments, CSF and peripheral blood, indicating different aberrations of immune function in the diseases and in the compartments. doi:10.1016/j.bbi.2009.05.029
27. Antiinflammatory therapy in psychiatric disorders Norbert Müller, Markus Schwarz Department of Psychiatry and Psychotherapy, University of Munich, LMU Munich, Germany A persistent (chronic) infection as aetiological factor in schizophrenia is discussed since many years. Signs of inflammation were observed in schizophrenic brains. Results of epidemiological studies showed that infection of the CNS in childhood increases the risk of becoming psychotic later on fivefold. Recent research points out that not one single pathogen but the immune response of the mother is related to the increased risk for schizophrenia. Several reports described increased serum IL-6 levels in schizophrenia. IL-6 is a product of activated monocytes and of the activation of the type-2 immune response. Moreover, several other signs of activation of the type-2 immune response are described in schizophrenia, while the type-1 immune response is decreased in the majority of schizophrenic patients. Mechanisms involved in the inflammatory process in schizophrenia will be outlined. Proinflammatory cytokines, such as IL-6, IL-1 and TNF appear to be elevated at least in the peripheral blood of depressed patients. Thus IDO activity may be enhanced in depressed patients through these cytokines. Although IL-6 does not directly act on IDO, its elevated levels in serum may contribute to IDO activation within the CNS by the stimulatory effect on PGE2, which acts as cofactor in the activation of IDO. This fits with a report on the correlation of increased in vitro IL-6 production with decreased tryptophan levels in depressed. Due to the increase of proinflammatory cytokines and PGE2 in some psychiatric patients, antiinflammatory treatment would be expected to show advantagous effects in schizophrenic and depressed patients. Possible therapeutic
strategies based on immune-modulatory effects including cyclooxygenase-2 inhibition will be discussed. doi:10.1016/j.bbi.2009.05.030
28. Changes in prolactin levels as predictor of response to treatment with aripiprazole Richard Musil, Michael Riedel, Ilja Spellmann, Markus Opgen-Rhein, Markus J. Schwarz Department of Psychiatry and Psychotherapy, University of Munich, LMU Munich, Germany Aripiprazole is a partial agonist at D2 receptors and has been shown to normalize antipsychotic-induced elevated prolactin levels. Changes in prolactin levels have previously been shown to correlate with symptom reduction in patients treated with typical anti-psychotics. In this study we were interested to see whether aripiprazole serum levels, doses or prolactin changes correlate with treatment response in schizophrenic patients. This was an open label eightweek trial evaluating 50 patients with DSM-IV diagnosis of schizophrenia. The patients were treated mono-therapeutically with aripiprazole. Efficacy was assessed weekly using the Positive and Negative Syndrome Scale (PANSS). Serum concentrations of aripiprazole and dehydro-aripiprazole were measured with HPLC and prolactin levels with ELECSYS (Roche Diagnostics). Aripiprazole showed significant improvement in PANSS total and all sub-scores between baseline and endpoint visit. Response to therapy did not correlate with dose (ANOVA: p = 0.953) or serum concentrations (aripiprazole: r = 0.002; dehydro-aripiprazole: r = 0.123). Prolactin levels decreased highly significant already within the first week of treatment with aripiprazole (T = 3.968; p < 0.001). Interestingly we found a differentiated and distinctive correlation between the reduction in prolactin levels within the first week of treatment and clinical improvement in PANSS global (r = 0.723; p = 0.002) and negative scores (r = 0.696; p = 0.003). Negative symptoms in schizophrenia were proposed to originate in increased dopamine efflux in the prefrontal cortex. The partial antagonistic effect of aripiprazole was hypothesized to normalize dopamine levels. The same mechanism might account for the inhibitory effect on prolactin secretion in the pituitary. Thus our results suggest a parallel antagonistic effect in different cortical regions. In this context prolactin might function as a predictor for therapy response to aripiprazole in the course of treatment. doi:10.1016/j.bbi.2009.05.031
29. Suppression of IL-6 production from cholinergic stimulated PBMS is connected to high expression of non-a-Bungarotoxin nicotine type of acetylcholine receptor on CD14+ cells A. Nast a, O. Malysheva b, A. Krause c, M. Wahle d, CGO. Baerwald b a Medizinische Department of Internal Medicine, Rheumatology and Clinical Immunology, Charité—University Hospital, Berlin, Germany b Department of Internal Medicine II, University Hospital Leipzig, Leipzig, Germany c Immanuel Hospital, Rheumatology Clinic, Berlin, Germany d Klinikum der Johann W. Goethe-Universität Frankfurt, Medical Clinic II, Frankfurt, Germany
Introduction: Increasing evidence indicates that PBMC possess a cholinergic system, consisting of different subtypes of cholinergic