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Fortschr Neurol Psychiatr 2009; 77(6): 334-345
DOI: 10.1055/s-0028-1109420
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Die Bedeutung des TNF-α-Systems für Erkrankungen des Gehirns

The Relevance of the TNF-α System in Psychiatric DisordersH. Himmerich1, 2 , M. Berthold-Losleben1 , T. Pollmächer3
  • 1Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum der RWTH Aachen
  • 2Klinik und Poliklinik für Psychiatrie, Universitätsklinikum Leipzig
  • 3Zentrum für psychische Gesundheit, Klinikum Ingolstadt
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Publication History

Publication Date:
04 May 2009 (online)

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Zusammenfassung

Es gibt vielfache Hinweise in der Literatur darauf, dass Veränderungen des Immunsystems oder spezifischer ausgedrückt des Zytokinsystems, zu dem auch der Tumornekrosefaktor-alpha (TNF-α) zählt, an der Entstehung neurologischer Erkrankungen aus dem entzündlichen und neurodegenerativen Formenkreis wie der Multiplen Sklerose, dem Morbus Alzheimer und Morbus Parkinson sowie psychiatrischer Erkrankungen wie der Depression, Schizophrenie und Narkolepsie beteiligt sind. Zudem bestehen Zusammenhänge zwischen Zytokinkonzentrationen im Serum und dem Risiko zereobrovaskulärer Ereignisse. Auch Körpergewicht, Alter und neuroendokrinologische Mechanismen haben einen starken Einfluss auf die Plasmakonzentrationen von TNF-α und seiner löslichen Rezeptoren (sTNF-Rs). TNF-α könnte zur Pathogenese dieser Erkrankungen durch eine Aktivierung der Hypothalamus-Hypophysen-Nebennierenrinden-Achse (HPA-Achse), eine Aktivierung von Serotonintransportern, eine Stimulation der Indolamin-2,3-Dioxygenase, die zur Tryptophandepletion führt, einen immunologisch vermittelten Neuronenuntergang oder neurotoxische Effekte durch Glutamatausschüttung beitragen. Auch eine psychopharmakologische Therapie beeinflusst das Immunsystem. Bei der antipsychotischen Therapie ist möglicherweise ein Teil der Wirkung bestimmter Antipsychotika über eine Induktion inflammatorischer Zytokine vermittelt. Es ist zu wünschen, dass diese Überlegungen in naher Zukunft zu immunmodulatorischen Therapiestrategien für psychisch kranke Patienten führen.

Abstract

Changes regarding the immune system and specifically the cytokine system, of which tumor necrosis factor-alpha (TNF-α) is a part, have been shown to be involved in the development of neurological and psychiatric disorders such as multiple sclerosis, Parkinson‘s and Alzheimer‘s disease, depression, schizophrenia or narcolepsy. Besides, there is evidence that the risk of stroke correlates with the serum concentrations of different cytokines. Additionally, body weight, age and neuroendocrinological mechanism have a strong influence upon plasma levels of TNF-α and its soluble receptors (sTNF-Rs). TNF-α might contribute to the pathogenesis of these diseases by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters, the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion, by immunologically mediated destruction of neurons, or neurotoxic release of glutamate. Psychotropic drugs influence the TNF-α system, too. During psychopharmacological treatment of schizophrenia, some antipsychotics might act on neurotransmitter metabolism via inducing the proinflammatory cytokine system. Hopefully, these hypotheses may lead to new therapeutical strategies for psychiatric patients in the near future.

Schlüsselwörter

TNF-α - Depression - Schizophrenie - Narkolepsie - Psychopharmaka - Zytokin - Entzündung

Key words

TNF-α - depression - schizophrenia - narcolepsy - psychopharmacology - cytokine - inflammation

Literatur

  • 1 Himmerich H. Neuroimmunologie. Holsboer F, Gründer G, Benkert O Handbuch der Psychopharmakologie Heidelberg; Springer 2007 1. Aufl: 369-374
    Google Scholar
  • 2 Fricchione G, Daly R, Rogers M P. et al . Neuroimmunologic influences in neuropsychiatric and psychophysiologic disorders.  Acta Pharmacol Sin. 2001;  22 577-587
    Google Scholar
  • 3 Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity.  Eur J Pharmacol. 2004;  500 399-411
    Google Scholar
  • 4 Harenberg Lexikon der Nobelpreisträger. Dortmund; Harenberg Lexikon Verlag 2000
    Google Scholar
  • 5 Carswell E A, Old L J, Kassel R L. et al . An endotoxin-induced serum factor that causes necrosis of tumors.  Proc Natl Acad Sci USA. 1975;  72 3666-3670
    Google Scholar
  • 6 Clark I A. How TNF was recognized as a key mechanism of disease.  Cytokine Growth Factor Rev. 2007;  18 335-343
    Google Scholar
  • 7 Goodsell D S. The molecular perspective: tumor necrosis factor.  Oncologist. 2006;  11 83-84
    Google Scholar
  • 8 Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level.  FEBS Lett. 1991;  285 199-212
    Google Scholar
  • 9 Perskidskiî I uV, Barshteiîn I uA. Biological manifestations of the tumor necrosis factor effect and its role in the pathogenesis of various diseases.  Arkh Patol. 1992;  54 5-10
    Google Scholar
  • 10 Himmerich H. Activity of the TNF-alpha system in patients with brain disorders and during psychopharmacological treatment.  Curr Pharmaceut Anal. 2007;  3 1-5
    Google Scholar
  • 11 Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling.  Cell Death Differ. 2003;  10 45-65
    Google Scholar
  • 12 Plümpe J, Malek N P, Bock C T. et al . NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration.  Am J Physiol Gastrointest Liver Physiol. 2000;  278 173-183
    Google Scholar
  • 13 Alikhani M, Alikhani Z, Raptis M. et al . TNF-alpha in vivo stimulates apoptosis in fibroblasts through caspase-8 activation and modulates the expression of pro-apoptotic genes.  J Cell Physiol. 2004;  201 341-348
    Google Scholar
  • 14 Reddy P, Slack J L, Davis R. et al . Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme.  J Biol Chem. 2000;  275 14608-14614
    Google Scholar
  • 15 Glossop J R, Dawes P T, Nixon N B. et al . Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis.  Arthritis Res Ther. 2005;  7 1227-1234
    Google Scholar
  • 16 Himmerich H, Fulda S, Linseisen J. et al . TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population.  Eur Cytokine Netw. 2006;  17 196-201
    Google Scholar
  • 17 Bastard J P, Maachi M, Lagathu C. et al . Recent advances in the relationship between obesity, inflammation, and insulin resistance.  Eur Cytokine Netw. 2006;  17 4-12
    Google Scholar
  • 18 Zeyda M, Farmer D, Todoric J. et al . Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production.  Int J Obes. 2007;  31 1420-1428
    Google Scholar
  • 19 Panagiotakos D B, Pitsavos C, Yannakoulia M. et al . The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study.  Atherosclerosis. 2005;  183 308-315
    Google Scholar
  • 20 Arzt E, Kovalovsky D, Igaz L M. et al . Functional cross-talk among cytokines, T-cell receptor, and glucocorticoid receptor transcriptional activity and action.  Ann N Y Acad Sci. 2000;  917 672-677
    Google Scholar
  • 21 Kapcala L P, Chautard T, Eskay R L. The protective role of the hypothalamic-pituitary-adrenal axis against lethality produced by immune, infectious, and inflammatory stress.  Ann N Y Acad Sci. 1995;  771 419-437
    Google Scholar
  • 22 Silverman M N, Pearce B D, Biron C A. et al . Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection.  Viral Immunol. 2005;  18 41-78
    Google Scholar
  • 23 Tilders F J, DeRijk R H, Van Dam A M. et al . Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals.  Psychoneuroendocrinology. 1994;  19 209-232
    Google Scholar
  • 24 Besedovsky H O, del Rey A. The cytokine-HPA axis feed-back circuit.  Z Rheumatol. 2000;  59 (Suppl 2) 26-30
    Google Scholar
  • 25 Reul J M, Labeur M S, Wiegers G J. et al . Altered neuroimmunoendocrine communication during a condition of chronically increased brain corticotropin-releasing hormone drive.  Ann N Y Acad Sci. 1998;  840 444-455
    Google Scholar
  • 26 Schöbitz B, Reul J M, Holsboer F. The role of the hypothalamic-pituitary-adrenocortical system during inflammatory conditions.  Crit Rev Neurobiol. 1994;  8 263-291
    Google Scholar
  • 27 Michie H R, Spriggs D R, Manogue K R. et al . Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings.  Surgery. 1988;  104 280-286
    Google Scholar
  • 28 Petrovsky N, McNair P, Harrison L C. Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications.  Cytokine. 1998;  10 307-312
    Google Scholar
  • 29 Conti B, Tabarean I, Andrei C. et al . Cytokines and fever.  Front Biosci. 2004;  9 1433-1449
    Google Scholar
  • 30 Plata-Salamán C R. 1998 Curt P. Richter Award. Brain mechanisms in cytokine-induced anorexia.  Psychoneuroendocrinology. 1999;  24 25-41
    Google Scholar
  • 31 Pessayre D, Berson A, Fromenty B. et al . Mitochondria in steatohepatitis.  Semin Liver Dis. 2001;  21 57-69
    Google Scholar
  • 32 Ledeen R W, Chakraborty G. Cytokines, signal transduction, and inflammatory demyelination: review and hypothesis.  Neurochem Res. 1998;  23 277-289
    Google Scholar
  • 33 Takeuchi H, Jin S, Wang J. et al . Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner.  J Biol Chem. 2006;  281 21362-21368
    Google Scholar
  • 34 Handa S. Concentrations of interleukin-1 beta, interleukin-6, interleukin-8 and TNF-alpha in cerebrospinal fluid from children with septic or aseptic meningitis.  Kurume Med J. 1992;  39 257-265
    Google Scholar
  • 35 Ichiyama T, Hayashi T, Nishikawa M. et al . Cerebrospinal fluid levels of soluble tumour necrosis factor receptor in acute encephalitis.  J Neurol. 1996;  243 457-460
    Google Scholar
  • 36 Ichiyama T, Hayashi T, Furukawa S. Cerebrospinal fluid concentrations of soluble tumor necrosis factor receptor in bacterial and aseptic meningitis.  Neurology. 1996;  46 837-838
    Google Scholar
  • 37 Mukai A O, Krebs V L, Bertoli C J. et al . TNF-alpha and IL-6 in the diagnosis of bacterial and aseptic meningitis in children.  Pediatr Neurol. 2006;  34 25-29
    Google Scholar
  • 38 Dulkerian S J, Kilpatrick L, Costarino A T. et al . Cytokine elevations in infants with bacterial and aseptic meningitis.  J Pediatr. 1995;  126 872-876
    Google Scholar
  • 39 Bociaga-Jasik M, Garlicki A, Kalinowska-Nowak A. et al . Concentration of proinflammatory cytokines (TNF-alpha, IL-8) in the cerebrospinal fluid and the course of bacterial meningitis.  Przegl Lek. 2004;  61 78-85
    Google Scholar
  • 40 Fida N M, Al-Mughales J, Farouq M. Interleukin-1alpha, interleukin-6 and tumor necrosis factor-alpha levels in children with sepsis and meningitis.  Pediatr Int. 2006;  48 118-124
    Google Scholar
  • 41 Babulas V, Factor-Litvak P, Goetz R. et al . Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia.  Am J Psychiatry. 2006;  163 927-929
    Google Scholar
  • 42 Ravi V, Parida S, Desai A. et al . Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients.  J Med Virol. 1997;  51 132-136
    Google Scholar
  • 43 Sergerie Y, Rivest S, Boivin G. Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis.  J Infect Dis. 2007;  196 853-860
    Google Scholar
  • 44 Mrak R E, Griffin W S. Potential inflammatory biomarkers in Alzheimer’s disease.  J Alzheimers Dis. 2005;  8 369-375
    Google Scholar
  • 45 Mrak R E, Griffin W S. Common inflammatory mechanisms in Lewy body disease and Alzheimer disease.  J Neuropathol Exp Neurol. 2007;  66 683-686
    Google Scholar
  • 46 Griffin W S, Liu L, Li Y. et al . Interleukin-1 mediates Alzheimer and Lewy body pathologies.  J Neuroinflammation. 2006;  3 5
    Google Scholar
  • 47 Lemere C A. A beneficial role for IL-1 beta in Alzheimer disease?.  J Clin Invest. 2007;  117 1483-1485
    Google Scholar
  • 48 Shaftel S S, Griffin W S, O’Banion M K. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective.  J Neuroinflammation. 2008;  5 7
    Google Scholar
  • 49 Rogers J T, Lahiri D K. Metal and inflammatory targets for Alzheimer’s disease.  Curr Drug Targets. 2004;  5 535-551
    Google Scholar
  • 50 Baranowska-Bik A, Bik W, Wolinska-Witort E. et al . Plasma beta amyloid and cytokine profile in women with Alzheimer’s disease.  Neuro Endocrinol Lett. 2008;  29 75-79
    Google Scholar
  • 51 Bonotis K, Krikki E, Holeva V. et al . Systemic immune aberrations in Alzheimer’s disease patients.  J Neuroimmunol. 2008;  193 183-187
    Google Scholar
  • 52 Guerreiro R J, Santana I, Brás J M. et al . Peripheral inflammatory cytokines as biomarkers in Alzheimer’s disease and mild cognitive impairment.  Neurodegener Dis. 2007;  4 406-412
    Google Scholar
  • 53 Griffin W S. Perispinal etanercept: potential as an Alzheimer therapeutic.  J Neuroinflammation. 2008;  5 3
    Google Scholar
  • 54 He P, Zhong Z, Lindholm K. et al . Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice.  J Cell Biol. 2007;  178 829-841
    Google Scholar
  • 55 Medeiros R, Prediger R D, Passos G F. et al . Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer’s disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein.  J Neurosci. 2007;  27 5394-5404
    Google Scholar
  • 56 Kim Y S, Joh T H. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease.  Exp Mol Med. 2006;  38 333-347
    Google Scholar
  • 57 Tansey M G, McCoy M K, Frank-Cannon T C. Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention.  Exp Neurol. 2007;  208 1-25
    Google Scholar
  • 58 Nagatsu T, Sawada M. Inflammatory process in Parkinson’s disease: role for cytokines.  Curr Pharm Des. 2005;  11 999-1016
    Google Scholar
  • 59 Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson’s disease.  J Neural Transm Suppl. 2006;  70 373-381
    Google Scholar
  • 60 Mogi M, Harada M, Riederer P. et al . Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients.  Neurosci Lett. 1994;  165 208-210
    Google Scholar
  • 61 Hirsch E C, Hunot S, Damier P. et al . Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration?.  Ann Neurol. 1998;  44 115-120
    Google Scholar
  • 62 Wu Y R, Feng I H, Lyu R K. et al . Tumor necrosis factor-alpha promoter polymorphism is associated with the risk of Parkinson’s disease.  Am J Med Genet B Neuropsychiatr Genet. 2007;  144B 300-304
    Google Scholar
  • 63 Nishimura M, Mizuta I, Mizuta E. et al . Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson’s disease.  Neurosci Lett. 2000;  284 73-76
    Google Scholar
  • 64 McCoy M K, Martinez T N, Ruhn K A. et al . Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease.  J Neurosci. 2006;  26 9365-9375
    Google Scholar
  • 65 Wu D C, Jackson-Lewis V, Vila M. et al . Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.  J Neurosci. 2002;  22 1763-1771
    Google Scholar
  • 66 Welsh P, Lowe G D, Chalmers J. et al . Associations of proinflammatory cytokines with the risk of recurrent stroke.  Stroke. 2008;  39 2226-2230
    Google Scholar
  • 67 Hoshi T, Kitagawa K, Yamagami H. et al . Relations of serum high-sensitivity C-reactive protein and interleukin-6 levels with silent brain infarction.  Stroke. 2005;  36 768-772
    Google Scholar
  • 68 Rubattu S, Speranza R, Ferrari M. et al . A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study.  Eur J Neurol. 2005;  12 989-993
    Google Scholar
  • 69 Waje-Andreassen U, Kråkenes J, Ulvestad E. et al . IL-6: an early marker for outcome in acute ischemic stroke.  Acta Neurol Scand. 2005;  111 360-365
    Google Scholar
  • 70 Rodríguez-Yáñez M, Castillo J. Role of inflammatory markers in brain ischemia.  Curr Opin Neurol. 2008;  21 353-357
    Google Scholar
  • 71 Jenny N S, Tracy R P, Ogg M S. et al . In the elderly, interleukin-6 plasma levels and the −174G>C polymorphism are associated with the development of cardiovascular disease.  Arterioscler Thromb Vasc Biol. 2002;  22 2066-2071
    Google Scholar
  • 72 Ridker P M, Rifai N, Stampfer M J. et al . Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.  Circulation. 2000;  101 1767-1772
    Google Scholar
  • 73 Harris T B, Ferrucci L, Tracy R P. et al . Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.  Am J Med. 1999;  106 506-512
    Google Scholar
  • 74 Park H S, Park J Y, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6.  Diabetes Res Clin Pract. 2005;  69 29-35
    Google Scholar
  • 75 Adamopoulos S, Parissis J, Karatzas D. et al . Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure.  J Am Coll Cardiol. 2002;  39 653-663
    Google Scholar
  • 76 Tanabe A, Nomura S. Pathophysiology of depression.  Nippon Rinsho. 2007;  65 1585-1590
    Google Scholar
  • 77 Haack M, Hinze-Selch D, Fenzel T. et al . Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.  J Psychiatr Res. 1999;  33 407-418
    Google Scholar
  • 78 Maes M, Song C, Lin A H. et al . Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion.  Neuropsychopharmacology. 1999;  20 370-379
    Google Scholar
  • 79 Pucak M L, Kaplin A I. Unkind cytokines: current evidence for the potential role of cytokines in immune-mediated depression.  Int Rev Psychiatry. 2005;  17 477-483
    Google Scholar
  • 80 Maes M, Scharpé S, Meltzer H Y. et al . Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression.  Psychiatry Res. 1993;  49 11-27
    Google Scholar
  • 81 O’Brien S M, Scott L V, Dinan T G. Cytokines: abnormalities in major depression and implications for pharmacological treatment.  Hum Psychopharmacol. 2004;  19 397-403
    Google Scholar
  • 82 Reichenberg A, Yirmiya R, Schuld A. et al . Cytokine-associated emotional and cognitive disturbances in humans.  Arch Gen Psychiatry. 2001;  58 445-452
    Google Scholar
  • 83 Reichenberg A, Kraus T, Haack M. et al . Endotoxin-induced changes in food consumption in healthy volunteers are associated with TNF-alpha and IL-6 secretion.  Psychoneuroendocrinology. 2002;  27 945-956
    Google Scholar
  • 84 Linthorst A C, Reul J M. Inflammation and brain function under basal conditions and during long-term elevation of brain corticotropin-releasing hormone levels.  Adv Exp Med Biol. 1999;  461 129-152
    Google Scholar
  • 85 Yirmiya R. Behavioral and psychological effects of immune activation: implications for depression due to a general medical condition.  Curr Opin Psychiatry. 1997;  10 470-476
    Google Scholar
  • 86 Schuld A, Schmid D A, Haack M. et al . Hypothalamo-pituitary-adrenal function in patients with depressive disorders is correlated with baseline cytokine levels, but not with cytokine responses to hydrocortisone.  J Psychiatr Res. 2003;  37 463-470
    Google Scholar
  • 87 Himmerich H, Binder E B, Künzel H E. et al . Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis.  Biol Psychiatry. 2006;  60 882-888
    Google Scholar
  • 88 Zhu C B, Blakely R D, Hewlett W A. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters.  Neuropsychopharmacology. 2006;  31 2121-2131
    Google Scholar
  • 89 Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans.  Int J Neuropsychopharmacol. 2002;  5 375-388
    Google Scholar
  • 90 Brown A S, Hooton J, Schaefer C A. et al . Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.  Am J Psychiatry. 2004;  161 889-895
    Google Scholar
  • 91 Brown A S, Begg M D, Gravenstein S. et al . Serologic evidence of prenatal influenza in the etiology of schizophrenia.  Arch Gen Psychiatry. 2004;  61 774-780
    Google Scholar
  • 92 Brown A S, Schaefer C A, Quesenberry C P. et al . Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring.  Am J Psychiatry. 2005;  162 767-773
    Google Scholar
  • 93 Buka S L, Cannon T D, Torrey E F. et al . Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring.  Biol Psychiatry. 2008;  63 809-815
    Google Scholar
  • 94 Gattaz W F, Abrahão A L, Foccacia R. Childhood meningitis, brain maturation and the risk of psychosis.  Eur Arch Psychiatry Clin Neurosci. 2004;  254 23-26
    Google Scholar
  • 95 Rantakallio P, Jones P, Moring J. et al . Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up.  Int J Epidemiol. 1997;  26 837-843
    Google Scholar
  • 96 Müller N, Riedel M, Ackenheil M. et al . Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation.  World J Biol Psychiatry. 2000;  1 173-179
    Google Scholar
  • 97 Wilke I, Arolt V, Rothermundt M. et al . Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients.  Eur Arch Psychiatry Clin Neurosci. 1996;  246 279-284
    Google Scholar
  • 98 Kammen, McAllister-Sistilli, Kelley. Relationship between immune and behavioral measures in schizophrenia. Wieselmann, G Current update in psychoimmunology Berlin, Heidelberg, New York; Springer 1997
    Google Scholar
  • 99 Müller N, Schwarz M J. Immunologische Aspekte bei schizophrenen Störungen.  Nervenarzt. 2007;  78 253-263
    Google Scholar
  • 100 Stone T W. Neuropharmacology of quinolinic and kynurenic acids.  Pharmacol Rev. 1993;  45 309-379
    Google Scholar
  • 101 Erhardt S, Schwieler L, Engberg G. Kynurenic acid and schizophrenia.  Adv Exp Med Biol. 2003;  527 155-165
    Google Scholar
  • 102 Erhardt S, Schwieler L, Nilsson L. et al . The kynurenic acid hypothesis of schizophrenia.  Physiol Behav. 2007;  92 203-209
    Google Scholar
  • 103 Schwarcz R, Rassoulpour A, Wu H Q. et al . Increased cortical kynurenate content in schizophrenia.  Biol Psychiatry. 2001;  50 521-530
    Google Scholar
  • 104 Müller N, Ulmschneider M, Scheppach C. et al . COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy.  Eur Arch Psychiatry Clin Neurosci. 2004;  254 14-22
    Google Scholar
  • 105 Müller N, Riedel M, Schwarz M J. Psychotropic effects of COX-2 inhibitors--a possible new approach for the treatment of psychiatric disorders.  Pharmacopsychiatry. 2004;  37 266-269
    Google Scholar
  • 106 Müller N, Riedel M, Scheppach C. et al . Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.  Am J Psychiatry. 2002;  159 1029-1034
    Google Scholar
  • 107 Müller N, Riedel M, Schwarz M J. et al . Clinical effects of COX-2 inhibitors on cognition in schizophrenia.  Eur Arch Psychiatry Clin Neurosci. 2005;  255 149-151
    Google Scholar
  • 108 Yokota O, Terada S, Ishihara T. et al . Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia.  Prog Neuropsychopharmacol Biol Psychiatry. 2004;  28 715-721
    Google Scholar
  • 109 Kato T, Monji A, Hashioka S. et al . Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro.  Schizophr Res. 2007;  92 108-115
    Google Scholar
  • 110 Potvin S, Stip E, Sepehry A A. et al . Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review.  Biol Psychiatry. 2008;  63 801-808
    Google Scholar
  • 111 Bresee C J, Delrahim K, Maddux R E. et al . The effects of celecoxib augmentation on cytokine levels in schizophrenia.  Int J Neuropsychopharmacol. 2006;  9 343-348
    Google Scholar
  • 112 Mayer G, Pollmächer T. Narkolepsie – Neue Chancen in Diagnostik und Therapie. Thieme 2007
    Google Scholar
  • 113 Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region.  J Neuroimmunol. 2001;  117 9-20
    Google Scholar
  • 114 Mignot E, Tafti M, Dement W C. et al . Narcolepsy and immunity.  Adv Neuroimmunol. 1995;  5 23-37
    Google Scholar
  • 115 Möller E, Böhme J, Valugerdi M A. et al . Speculations on mechanisms of HLA associations with autoimmune diseases and the specificity of „autoreactive” T lymphocytes.  Immunol Rev. 1990;  118 5-19
    Google Scholar
  • 116 Dauvilliers Y. Neurodegenerative, autoimmune and genetic processes of human and animal narcolepsy.  Rev Neurol. 2003;  159 83-87
    Google Scholar
  • 117 Thannickal T C, Moore R Y, Nienhuis R. et al . Reduced number of hypocretin neurons in human narcolepsy.  Neuron. 2000;  27 469-474
    Google Scholar
  • 118 Hohjoh H, Nakayama T, Ohashi J. et al . Significant association of a single nucleotide polymorphism in the tumor necrosis factor-alpha (TNF-alpha) gene promoter with human narcolepsy.  Tissue Antigens. 1999;  54 138-145
    Google Scholar
  • 119 Himmerich H, Beitinger P A, Fulda S. et al . Plasma levels of tumor necrosis factor alpha and soluble tumor necrosis factor receptors in patients with narcolepsy.  Arch Intern Med. 2006;  166 1739-1743
    Google Scholar
  • 120 Hinze-Selch D, Schuld A, Kraus T. et al . 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.  Neuropsychopharmacology. 2000;  23 13-19
    Google Scholar
  • 121 Kraus T, Haack M, Schuld A. et al . Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine.  Pharmacopsychiatry. 2002;  35 220-225
    Google Scholar
  • 122 Pollmächer T, Hinze-Selch D, Mullington J. Effects of clozapine on plasma cytokine and soluble cytokine receptor levels.  J Clin Psychopharmacol. 1996;  16 403-409
    Google Scholar
  • 123 Schuld A, Kraus T, Haack M. et al . Plasma levels of cytokines and soluble cytokine receptors during treatment with olanzapine.  Schizophr Res. 2000;  43 164-166
    Google Scholar
  • 124 Maes M, Song C, Lin A H. et al . In vitro immunoregulatory effects of lithium in healthy volunteers.  Psychopharmacology. 1999;  143 401-407
    Google Scholar
  • 125 Himmerich H, Koethe D, Schuld A. et al . Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium.  Psychopharmacology. 2005;  179 447-451
    Google Scholar
  • 126 Kraus T, Haack M, Schuld A. et al . Body weight and leptin plasma levels during treatment with antipsychotic drugs.  Am J Psychiatry. 1999;  156 312-314
    Google Scholar
  • 127 Pollmächer T, Hinze-Selch D, Fenzel T. et al . Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol.  Am J Psychiatry. 1997;  154 1763-1765
    Google Scholar
  • 128 Brustolim D, Ribeiro-dos-Santos R, Kast R E. et al . A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice.  Int Immunopharmacol. 2006;  6 903-907
    Google Scholar
  • 129 Himmerich H, Schuld A, Haack M. et al . Early prediction of changes in weight during six weeks of treatment with antidepressants.  J Psychiatr Res. 2004;  38 485-489
    Google Scholar
  • 130 Davis M. Hepatotoxicity of antidepressants.  Int Clin Psychopharmacol. 1991;  6 97-103
    Google Scholar
  • 131 Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs.  Hepatology. 1999;  29 1347-1351
    Google Scholar
  • 132 Himmerich H, Kaufmann C, Schuld A. et al . Elevation of liver enzyme levels during psychopharmacological treatment is associated with weight gain.  J Psychiatr Res. 2005;  39 35-42
    Google Scholar
  • 133 Choi I, Kang H S, Yang Y. et al . IL-6 induces hepatic inflammation and collagen synthesis in vivo.  Clin Exp Immunol. 1994;  95 530-535
    Google Scholar
  • 134 Ikejima K, Takei Y, Honda H. et al . Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat.  Gastroenterology. 2002;  122 1399-1410
    Google Scholar
  • 135 Tilg H. Cytokines and liver diseases.  Can J Gastroenterol. 2001;  15 661-668
    Google Scholar
  • 136 Müller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission.  Neurotox Res. 2006;  10 131-148
    Google Scholar
  • 137 Pollmächer T, Schuld A, Kraus T. et al . Zur klinischen Relevanz der Wirkung von Clozapin auf die Freisetzung von Zytokinen und löslichen Zytokinrezeptoren.  Fortschr Neurol Psychiatr. 2001;  69 (Suppl 2) 65-74
    Google Scholar
  • 138 Tyring S, Gottlieb A, Papp K. et al . Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial.  Lancet. 2006;  367 29-35
    Google Scholar
  • 139 Uguz F, Akman C, Kucuksarac S. et al . Anti-tumor necrosis factor-alpha therapy is associated with less frequent mood and anxiety disorders in patients with rheumatoid arthritis.  Psychiatry Clin Neurosci. 2009;  63 50-55
    Google Scholar
  • 140 Ricart E, García-Bosch O, Ordás I. et al . Are we giving biologics too late? The case for early versus late use.  World J Gastroenterol. 2008;  14 5523-5527
    Google Scholar
  • 141 Bongartz T, Sutton A J, Sweeting M J. et al . Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.  JAMA. 2006;  295 2275-2285
    Google Scholar
  • 142 Nasir A, Greenberg J D. TNF antagonist safety in rheumatoid arthritis: updated evidence from observational registries.  Bull NYU Hosp Jt Dis. 2007;  65 178-181
    Google Scholar
  • 143 Solomon D H, Karlson E W, Rimm E B. et al . Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis.  Circulation. 2003;  107 1303-1307
    Google Scholar
  • 144 Wolfe F, Freundlich B, Straus W L. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis.  J Rheumatol. 2003;  30 36-40
    Google Scholar
  • 145 Efimov G A, Kruglov A A, Tillib S V. et al . Tumor Necrosis Factor and the consequences of its ablation in vivo.  Mol Immunol. 2009;  Epub 19.2.2009
    Google Scholar
  • 146 Sperner-Unterweger B. Biologische Hypothesen zur Schizophrenie: Mögliche Einflüsse von Immunologie und Endokrinologie.  Fortschr Neurol Psychiatr. 2005;  73 (Suppl 1) 38-43
    Google Scholar
  • 147 Fromont A, De Seze J, Fleury M C. et al . Inflammatory demyelinating events following treatment with anti-tumor necrosis factor.  Cytokine. 2009;  45 55-57
    Google Scholar

Prof. Dr. med. Hubertus Himmerich

Klinik und Poliklinik für Psychiatrie, Universitätsklinikum Leipzig, AöR

Semmelweisstraße 10

04107 Leipzig

Email: Hubertus.Himmerich@medizin.uni-leipzig.de

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