치료 저항성 조현병 환자와 치료 반응성 조현병 환자간의 CRP를 포함한 염증 표지자 비교 = Comparison of Inflammatory Markers Including C-Reactive Protein between Treatment Resistant Schizophrenia and Non-Treatment Resistant Schizophrenia

다국어 초록 (Multilingual Abstract)

Objectives：The present study is to investigate inflammatory markers and associated clinical factors between treatment resistant schizophrenia and non-treatment resistant schizophrenia. Methods：Of the 116 schizophrenia subjects who were hospitalized for acute symptomatic treatment, 19 patients (16%) were treated with clozapine as a treatment resistant schizophrenia(TRS) and 97 patients(84%) were treated with other atypical antipsychotics as a non-treatment resistant schizophrenia(Non-TRS). Various inflammatory markers including C-reactive protein(CRP) and clinical factors were retrospectively evaluated with electrical medical records. Results：There were significant differences between two groups in disease duration( p =0.015), number of admission ( p =0.003), Clinical Global Impression( p ＜0.001) but other demographic and clinical variables including previous antipsychotics use did not show significant differences. In terms of hematologic profiles, TRS group demonstrated higher CRP level( p =0.006), lower neutrophil count( p =0.012), and lower hemoglobin level( p =0.003) compared with non-TRS group. Body mass index was significantly correlated with CRP(r=0.318, p =0.001). Conclusion：The elevated level of serum CRP in TRS suggests that treatment resistance in schizophrenia may be associated with inflammatory response. However, retrospective study design and small number of subjects could limit this interpretation.

참고문헌 (Reference)

1 김의태, "치료 저항성 조현병의 이해와 치료" 대한신경정신의학회 57 (57): 230-234, 2018

2 김계환, "조현병 및 조현정동장애 입원환자에서 혈청 염증표지자와 정신병적 증상과의 관련성" 대한생물정신의학회 19 (19): 193-198, 2012

3 Mouchlianitis E, "Treatment-resistant schizophrenia patients show elevated anterior cingulate cortex glutamate compared to treatment-responsive" 42 : 744-752, 2016

4 Chamberlain SR, "Treatment-resistant depression and peripheral C-reactive protein" 214 : 11-19, 2019

5 Sanacora G, "Towards a glutamate hypothesis of depression : an emerging frontier of neuropsychopharmacology for mood disorders" 62 : 63-77, 2012

6 Kennedy JL, "The social and economic burden of treatment-resistant schizophrenia : a systematic literature review" 29 : 63-76, 2014

7 Wener MH, "The influence of age, sex, and race on the upper reference limit of serum C-reactive protein concentration" 27 : 2351-2359, 2000

8 Busner J, "The clinical global impressions scale : applying a research tool in clinical practice" 4 : 28-, 2007

9 Lin A, "T he i nflammatory response system i n treatment-resistant schizophrenia : increased serum interleukin-6" 32 : 9-15, 1998

10 Singh B, "Role of C-reactive protein in schizophrenia : an overview" 216 : 277-285, 2014

11 Park HS, "Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-α and IL-6" 69 : 29-35, 2005

12 Zahorec R, "Ratio of neutrophil to lymphocyte countsrapid and simple parameter of systemic inflammation and stress in critically ill" 102 : 5-14, 2001

13 Ali I, "Prevalence of Anemia among Schizophrenic Patients in Palestine" 7 : 6-, 2017

14 Özdin S, "Neutrophil/lymphocyte, platelet/lymphocyte and monocyte/lymphocyte ratios in different stages of schizophrenia" 271 : 131-135, 2019

15 Rettenbacher MA, "Neutropenia induced by second generation antipsychotics : a prospective investigation" 43 : 41-44, 2010

16 Tilleux S, "Neuroinflammation and regulation of glial glutamate uptake in neurological disorders" 85 : 2059-2070, 2007

17 Duncan GE, "Metabolic mapping of the rat brain after subanesthetic doses of ketamine : potential relevance to schizophrenia" 787 : 181-190, 1998

18 Veerman SR, "Memantine augmentation in clozapine-refractory schizophrenia:a randomized, double-blind, placebo-controlled crossover study" 46 : 1909-1921, 2016

19 Pearson TA, "Markers of inflammation and cardiovascular disease : application to clinical and public health practice : a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association" 107 : 499-511, 2003

20 Frydecka D, "Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation" 265 : 449-459, 2015

21 Fineberg AM, "Inflammatory cytokines and neurological and neurocognitive alterations in the course of schizophrenia" 73 : 951-966, 2013

22 Müller N, "Inflammation in schizophrenia" 49-68, 2012

23 Suvisaari J, "Inflammation in psychotic disorders : a population-based study" 189 : 305-311, 2011

24 Hefner G, "Inflammation and psychotropic drugs : the relationship between C-reactive protein and antipsychotic drug levels" 233 : 1695-1705, 2016

25 Strawbridge R, "Inflammation and clinical response to treatment in depression : a meta-analysis" 25 : 1532-1543, 2015

26 Maes M, "Increased serum interleukin-8and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor" 54 : 281-291, 2002

27 Müller N, "Immunology of schizophrenia" 21 : 109-116, 2014

28 Yuen EY, "Homeostatic regulation of glutamatergic transmission by dopamine D4 receptors" 107 : 22308-22313, 2010

29 Fan X, "Elevated serum levels of C-reactive protein are associated with more severe psychopathology in a subgroup of patients with schizophrenia" 149 : 267-271, 2007

30 Bustan Y, "Elevated neutrophil to lymphocyte ratio in non-affective psychotic adolescent inpatients : evidence for early association between inflammation and psychosis" 262 : 149-153, 2018

31 Maes M, "Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics" 10 : 119-124, 2000

32 Howes OD, "Dopamine synthesis capacity before onset of psychosis : a prospective [18F]-DOPA PET imaging study" 168 : 1311-1317, 2011

33 Ida T, "Cytokine-induced enhancement of calcium-dependent glutamate release from astrocytes mediated by nitric oxide" 432 : 232-236, 2008

34 Zhang XY, "Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia : association with psychopathology and response to antipsychotics" 30 : 1532-, 2005

35 Haroon E, "Conceptual convergence : increased inflammation is associated with increased basal ganglia glutamate in patients with major depression" 21 : 1351-, 2016

36 Joshi I, "Coincident activation of metabotropic glutamate receptors and NMDA receptors(NMDARs)downregulates perisynaptic/extrasynaptic NMDARs and enhances high-fidelity neurotransmission at the developing calyx of Held synapse" 27 : 9989-9999, 2007

37 Alvir JM, "Clozapine-induced agranulocytosis--incidence and risk factors in the United States" 329 : 162-167, 1993

38 Tanahashi S, "Clozapine, but not haloperidol, enhances glial D-serine and L-glutamate release in rat frontal cortex and primary cultured astrocytes" 165 : 1543-1555, 2012

39 Löffler S, "Clozapine therapy raises serum concentrations of high sensitive C-reactive protein in schizophrenic patients" 25 : 101-106, 2010

40 Guy W, "Clinical global impression" 217-222, 1976

41 Woods SW, "Chlorpromazine equivalent doses for the newer atypical antipsychotics" 64 : 663-667, 2003

42 Ridker PM, "C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women" 107 : 391-397, 2003

43 Horsdal HT, "C-reactive protein levels and treatment resistance in schizophrenia-A Danish population-based cohort study" 32 : e2632-, 2017

44 Fernandes BS, "C-reactive protein is increased in schizophrenia but is not altered by antipsychotics : metaanalysis and implications" 21 : 554-, 2016

45 Dickerson F, "C-reactive protein is elevated in schizophrenia" 143 : 198-202, 2013

46 Fond G, "C-Reactive Protein as a peripheral biomarker in schizophrenia. An updated systematic review" 9 : 392-, 2018

47 Müller N, "Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia" 159 : 1029-1034, 2002

48 Wannamethee SG, "Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease" 26 : 1765-1773, 2005

49 Seeman P, "Antipsychotic drugs : direct correlation between clinical potency and presynaptic action on dopamine neurons" 188 : 1217-1219, 1975

50 Uher R, "An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline" 171 : 1278-1286, 2014

51 Nitta M, "Adjunctive use of nonsteroidal antiinflammatory drugs for schizophrenia : a meta-analytic investigation of randomized controlled trials" 39 : 1230-1241, 2013

52 Kinney DK, "A unifying hypothesis of schizophrenia:abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction" 74 : 555-563, 2010

53 Bliss TV, "A synaptic model of memory : long-term potentiation in the hippocampus" 361 : 31-, 1993