Efekat antipsihotika na nespecifične markere inflamacije u prvoj epizodi shizofrenije
Sažetak
Uvod/Cilj. U razmatranju još uvek nepoznate etiologije shizofrenije, disfunkcija imunskog sistema koja uključuje i inflamaciju zauzima značajno mesto. Cilj našeg rada bio je da se odrede koncentracije nespecifičnih markera zapaljenja u krvi, u prvoj epizodi shizofrenije i njihova povezanost sa terapijskim odgovorom na antipsihotike. Metode. U radu smo određivali koncentracije nespecifičnih markera zapaljenja u krvi: leukocita (WBC), C-reaktivnog proteina (CRP), sedimentacije eritrocita (SE) i elemenata leukocitarne formule: granulocita (Gra), limfocita (Lym) i monocita (Mon), i to u prvoj epizodi šizofrenije, kod 78 hospitalizovanih bolesnika u Klinici za psihijatrijske bolesti „Dr Laza Lazarević” u Beogradu. Njihove koncentracije određivali smo pri prijemu i četiri sedmice nakon antipsihotičke terapije. Težinu psihopatologije i farmakoterapijski odgovor pratili smo primenom Skale pozitivnih i negativnih sindroma shizofrenije (Positive and negative syndrome scale for schizophrenia – PANSS). Rezultati. U prvoj epizodi shizofrenije, pre uvođenja antipsihotika, postojala je visoka učestalost abnormalnih laboratorijskih vrednosti (≥ 25% bolesnika) sledećih nespecifičnih markera inflamacije: WBC, CRP i SE, kao i Gra u leukocitarnoj formuli, ali i smanjenje svih njih nakon četiri sedmice antipsihotičke terapije, na nivou visoke statističke značajnosti za WBC i Gra (p < 0.001). Sedimentacija eritrocita ostala je povećana kod čak 50% bolesnika i nakon 4-sedmičnog antipsihotičkog lečenja, na nivou statističke značajnosti kod onih koji nisu reagovali na terapiju u odnosu na one koji jesu (p = 0.045 ). Zaključak. Dobijeni rezultati pokazuju da u prvoj epizodi shizofrenije kod subpopulacije bolesnika postoje povećane vrednosti nespecifičnih markera inflamacije u krvi (WBC, CRP , SE i Gra iz leukocitarne formule), sa tendencijom njihove normalizacije nakon četiri sedmice antipsihotičkog tretmana.
Ključne reči:
shizofrenija; antipsihotici; zapaljenje, medijatori; osetljivost i specifičnost; testovi, prognostička vrednost.Reference
Nagai T, Ibi D, Yamada K. Animal model for schizophrenia that reflects gene-environment interactions. Biol Pharm Bull 2011; 34(9): 1364−8.
Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci 2009; 63(3): 257−65.
Bessis A, Béchade C, Bernard D, Roumier A. Microglial control of neuronal death and synaptic properties. Glia 2007; 55(3): 233−8.
Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA 2005; 102(28): 9936−41.
Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature 2006; 440(7087): 1054−9.
Roberts RC, Roche JK, Conley RR. Synaptic differences in the postmortem striatum of subjects with schizophrenia: a stereological ultrastructural analysis. Synapse 2005; 56(4): 185−97.
Dunjic-Kostic B, Jasovic-Gasic M, Ivkovic M, Radonjic NV, Pantovic M, Damjanovic A, et al. Serum levels of interleukin-6 and tumor necrosis factor-alpha in exacerbation and remission phase of schizophrenia. Psychiatr Danub 2013; 25(1): 55−61.
Meyer U. Anti-inflammatory signaling in schizophrenia. Brain Behav Immun 2011; 25(8): 1507−18.
Müller N, Myint AM, Krause D, Weidinger E, Schwarz MJ. Anti-inflammatory treatment in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2013; 5(42): 146−53.
Borovcanin M, Jovanovic I, Radosavljevic G, Djukic Dejanović S, Stefanovic V, Arsenijevic N, et al. Antipsychotics can modulate the cytokine profile in schizophrenia: attenuation of the type-2 inflammatory response. Schizophr Res 2013; 147(1): 103−9.
Keller WR, Kum LM, Wehring HJ, Koola MM, Buchanan RW, Kelly DL. A review of anti-inflammatory agents for symptoms of schizophrenia. J Psychopharmacol 2013; 27(4): 337−42.
Miller CL, Llenos IC, Dulay JR, Barillo MM, Yolken RH, Weis S. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol Dis 2004; 15(3): 618−29.
Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry 2014; 75(4): 324−31.
Peet M. The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia. Prostaglandins Leukot Essent Fatty Acids 2006; 75(4−5): 323−7.
Suvisaari J, Mantere O. Inflammation theories in psychotic disorders: a critical review. Infect Disord Drug Targets 2013; 13(1): 59−70.
Mitchell AJ, Vancampfort D, Sweers K, van Winkel R, Yu W, de Hert M. Prevalence of metabolic syndrome and metabolic abnormalities in schizophrenia and related disorders--a systematic review and meta-analysis. Schizophr Bull 2013; 39(2): 306−18.
Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull 2014; 40(1): 181−91.
Na KS, Kim WH, Jung HY, Ryu SG, Min KJ, Park KC, et al. Relationship between inflammation and metabolic syndrome following treatment with paliperidone for schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2012; 39(2): 295−300.
Sperner-Unterweger B, Whitworth A, Kemmler G, Hilbe W, Thaler J, Weiss G, et al. T-cell subsets in schizophrenia: a comparison between drug-naive first episode patients and chronic schizophrenic patients. Schizophr Res 1999; 38(1): 61−70.
Zorrilla EP, Cannon TD, Gur RE, Kessler J. Leukocytes and organ-nonspecific autoantibodies in schizophrenics and their siblings: markers of vulnerability or disease. Biol Psychiatry 1996; 40(9): 825−33.
Fan X, Liu EY, Freudenreich O, Park JH, Liu D, Wang J, et al. Higher white blood cellcounts are associated with an increased risk for metabolic syndrome and more severe psychopathology in non-diabetic patients with schizophrenia. Schizophr Res 2010; 118(1−3): 211−7.
Miller BJ, Gassama B, Sebastian D, Buckley P, Mellor A. Meta-analysis of lymphocytes in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 2013; 73(10): 993−9.
Steiner J, Gos T, Bogerts B, Bielau H, Drexhage HA, Bernstein H. Possible impact of microglial cells and the monocyte-macrophage system on suicidal behavior. CNS Neurol Disord Drug Targets 2013; 12(7): 971−9.
Dimitrov DH. Correlation or coincidence between monocytosis and worsening of psychotic symptoms in veterans with schizophrenia. Schizophr Res 2011; 126(1−3): 306−7.
Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yang S, et al. C-reactive protein is elevated in schizophrenia. Schizophr Res 2013; 143(1): 198−202.
Miller BJ, Mellor A, Buckley P. Total and differential white blood cell counts, high-sensitivity C-reactive protein, and the metabolic syndrome in non-affective psychoses. Brain Behav Immun 2013; 31: 82−9.
Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. C-reactive protein is associated with the severity of cognitive impairment but not of psychiatric symptoms in individuals with schizophrenia. Schizophr Res 2007; 93(1−3): 261−5.
Fan X, Pristach C, Liu EY, Freudenreich O, Henderson DC, Goff DC. Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia. Psychiatry Res 2007; 149(1−3): 267−71.
Pavlović M, Babić D, Rastović P, Ljevak I. Association of erythrocyte sedimentation rate and fibrinogen concentration with metabolic syndrome in a schizophrenic patients. Psychiatr Danub 2013; 25(Suppl 1): 51−5.
Melamed Y, Sirota P. Erythrocyte sedimentation rate in patients with schizophrenia. Can J Psychiatry 2000; 45(10): 938.
Dean B. Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies. Int J Neuropsychopharmacol 2011; 14(7): 997−1012.
Kelly DL, Conley RR, Love RC, Morrison JA, McMahon RP. Metabolic risk with second-generation antipsychotic treatment: a double-blind randomized 8-week trial of risperidone and olanzapine. Ann Clin Psychiatry 2008; 20(2): 71−8.
Leucht S, Davis JM, Engel RR, Kane JM, Wagenpfeil S. Defining 'response' in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology 2007; 32(9): 1903−10.
Thomas SP, Nandhra HS, Singh SP. Pharmacologic treatment of first-episode schizophrenia: a rewiew of the literature. Prim Care Companion CNS Disord 2012; 14(1): pii: PCC.11r01198.
Na KS, Jung HY, Kim YK. The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2014; 48:277−86.
Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS. Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun 2006; 20(6): 532−45.
Blasco-Fontecilla H, Baca-Garcia E, de Leon J. Do atypical antipsychotic drugs reduce the risk of ischemic heart disease and mortality? Possible role of 5-HT2A receptor blockade. Schizophr Res 2010; 119(1−3): 160−3.
Nitta M, Kishimoto T, Müller N, Weiser M, Davidson M, Kane JM, et al. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull 2013; 39(6): 1230−41.