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An autoimmune or an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives
Schizophrenia Research 84 (2006) 180 – 182 www.elsevier.com/locate/schres
Letter to the Editors
An autoimmune or an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives Dear Editors, Elevated serum levels of the potent stimulant of antibody production interleukin-6 (IL-6) were described especially in patients with schizophrenia with predominant negative symptoms and/or poor therapy outcome (Schwarz et al., 2001). An increased antibody production led to the discussion of an autoimmune origin of schizophrenia. Antibodies against brain structures such as hippocampus, septum, cingulated gyrus, amygdala, and frontal cortex, or non-specific autoantibodies have been observed in schizophrenia (Rothermundt et al., 2001). The goals of the present study were to determine possible inflammatory or autoimmune processes in patients with schizophrenia, schizoaffective disorder, and in their biological relatives, by means of the assessment of serum levels of interleukin-6 (IL-6), and antibodies against hippocampus. The subjects were 50 patients with schizophrenia, schizoaffective disorder, outpatients, and were in remission, in chronic treatment with typical antipsychotic and atypical antipsychotic agents. 50 healthy volunteer controls, 48 relatives with mood disorders, and 41 relatives without mental disorders were also studied. The Ethics Research Committee of Londrina State University approved the research. The patients, volunteers, and relatives were interviewed by structured diagnostic criteria, categorized according to the criteria of the fourth edition of the American Psychiatric Association’s Diagnostic and 0920-9964/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.02.003
Statistical Manual of Mental Disorders or DSM-IV, Axis I (SCID-IV), translated into Portuguese by Del Bem et al. (2001). Anti-hippocampus IgG was measured by enzymelinked immunosorbent assay (ELISA), using antigen from human hippocampus. Serum interleukin-6 (IL-6) was measured by chemoluminescent immunoenzymatic assay methods (ImmuliteR IL-6, Diagnostic Products Corporation, Los Angeles, CA, USA), with values of 0–5.4pg/mL. No significant difference in age was found between the four groups of subjects ( F = 0.19, df = 3, p = 0.900). The four groups did not differ significantly from each other with respect to gender (v 2 = 7.52, df = 3, p = 0.057). The groups were significantly different concerning educational background, occupational impairment, and marital status. Patients were significantly lower in educational level than controls and relatives (v 2 = 13.3, df = 3, p = 0.004). Most patients were unmarried (v 2 = 16.3, df = 3, p b 0.001), in contrast to controls and relatives. Occupational impairment was significantly higher in patients than in controls and relatives (v 2 = 133.2, df = 3, p b 0.001). The illness mean duration was 15.3 F 9.9years, and the median age of onset was 22.4 F 7.4 years. A higher percentage of patients had suicide attempts than controls, relatives without psychiatric disease, and relatives with humor disorder ( p b 0.001, Fisher’s exact test). Psychiatry hospitalizations were higher in patients than in controls, relatives without psychiatric disease, and relatives with humor disorder ( p b 0.001, Fisher’s exact test). Data showed no significant differences between groups concerning body mass index (BMI in kg/m2) ( F = 2.4, df = 3, p = 0.071, ANOVA).
Letter to the Editors
181
Table 1 Levels of interleukin-6 and antibodies against hippocampus in patients, relatives with mood disorder, relatives without mental disorder, and controls Variables
IL-6 Autoantibodies against hippocampus
Patients (n = 50)
Controls (n = 48)
Relatives without mental disorder (n = 41)
Relatives with mood disorder (n = 48)
Analysis
Median (range)
Median (range)
Median (range)
Median (range)
H
df
p
33.0a (4.9–1145) 0.147 (0.05–0.7)
5.0 (4.9–276) 0.135 (0.07–0.26)
27.3 (8.3–133) 0.144 (0.07–0.59)
54.5a (5.0–320) 0.152 (0.06–0.36)
11.78 2.16
3 3
0.008 0.540
H = Kruskal–Wallis test; df = degree of freedom. Autoantibodies = OD 492nm; IL-6 = 0–5.4pg/mL. a Dunn’s Test (significantly higher than in relatives without mental disorder and controls).
There were no statistically significant differences between groups in albumin ( F = 0.57, df = 3, p =0.637, ANOVA). Patients and relatives had higher, but not significantly, autoantibodies against hippocampus than controls (H = 2, 16, df = 3, p = 0.540, Kruskal–Wallis test) (Table 1). IL-6 was significantly higher in patients and relatives with mood disorder than in relatives without mental disorder and controls (H = 11.78, df = 3, p = 0.008, Kruskal–Wallis test followed by Dunn) (Table 1). The increased seric levels of IL-6, a pro-inflammatory cytokine, was observed in schizophrenic patients at a higher rate compared to controls in concordance with literature data (Lin et al., 1998; Rothermundt et al., 2001; Maes et al., 2000, 2002). IL-6 alterations may also occur in patients with schizophrenia, schizoaffective disorder with an unfavorable course of the disorder, longer duration of illness, treatment resistance, or more marked paranoid–hallucinatory symptomatology (Mu¨ller et al., 2000), rendering the importance of investigating it as one of the possible indicators that could be helpful in determining the evolution of the disease. In this study, it has been demonstrated that patients were chronically ill (duration of disorder 15.3 years), had early disorder onset (22.4 years), had more suicide attempts, more hospitalizations, worse occupational history, higher frequency of being unmarried, and those with lower educational background years had the poorest prognosis who were chronically ill. However, the possible involvement of an immunological or an inflammatory process in schizophrenics and their first-degree relatives with humor
disorder could be explained by genetic origin, which might be associated with viral infection/viral reactivation or to an autoimmune process. In that sense, the higher frequency of HLA.B415 was observed in these patients and relatives with and without mental disorders than in controls (Nunes et al., 2005). The findings suggest the existence of some involvement of an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives. References Del Bem, C., Vilela, J., Crippa, J., Labate, C., Zuardi, A., 2001. Confiabilidade da bentrevistaclı´nica estruturada para o D.S.M.IVQ. Rev. Bras. Psiquiatr. 23, 156 – 159 (Versa˜o clı´nica traduzida para o portugueˆs). Lin, A., Kenis, G., Bignotti, S., Tura, G., De Jong, R., Bosmans, E., Pioli, R., Altamura, C., Scharpe´, S., Maes, M., 1998. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr. Res. 32, 9 – 15. Maes, M., Chiavetto, L., Bignotti, S., Tura, G., Pioli, R., Boin, F., et al., 2000. Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur. Neuropsychopharmacol. 10, 119 – 124. Maes, M., Chiavetto, L., Bignotti, S., Tura, G., Pioli, R., Boin, F., et al., 2002. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr. Res. 54, 281 – 291. Mu¨ller, N., Riedel, M., Ackenheil, M., Schwarz, M., 2000. Cellular and humoral immune system in schizophrenia: a conceptual reevaluation. World J. Biol. Psychiatr. 1, 173 – 179. Nunes, S.O.V., Borelli, S., Matsuo T., Watanabe, M.A, Itano, E.N., 2005. The association of the HLA in patients with schizophrenia, schizoaffective disorder, and their biological relatives. Schizophrenia Research;{s.l.}.76: (.2/3), 195–198
182
Letter to the Editors
Rothermundt, M., Arolt, V., Bayer, T., 2001. Review of immunological and immunopathological findings in schizophrenia. Brain Behav. Immunol. 15, 319 – 339. Schwarz, M., Mu¨ller, N., Riedel, M., Ackenheil, M., 2001. The Th2-hypothesis of schizophrenia: a strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med. Hypotheses 56, 483 – 486.
Sandra O.V. Nunes Department of Psychiatry – Londrina State University (UEL), Brazil Corresponding author. Universidade Estadual de Londrina, Av. Adhemar de Barros, n8 625, 86050-190 – Londrina – Parana´ – Brazil. Tel.: +55 43 33390404; fax: +55 43 33238210. E-mail address: [email protected].
Tiemi Matsuo Department of Statistics and Applied Mathematics (UEL), Brazil Mari S. Kaminami Maria Ange´lica E. Watanabe Edna Maria V. Reiche Eiko N. Itano Department of Pathology, Clinical Analysis and Toxicology, Brazil 22 November 2005
Letter to the Editors
An autoimmune or an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives Dear Editors, Elevated serum levels of the potent stimulant of antibody production interleukin-6 (IL-6) were described especially in patients with schizophrenia with predominant negative symptoms and/or poor therapy outcome (Schwarz et al., 2001). An increased antibody production led to the discussion of an autoimmune origin of schizophrenia. Antibodies against brain structures such as hippocampus, septum, cingulated gyrus, amygdala, and frontal cortex, or non-specific autoantibodies have been observed in schizophrenia (Rothermundt et al., 2001). The goals of the present study were to determine possible inflammatory or autoimmune processes in patients with schizophrenia, schizoaffective disorder, and in their biological relatives, by means of the assessment of serum levels of interleukin-6 (IL-6), and antibodies against hippocampus. The subjects were 50 patients with schizophrenia, schizoaffective disorder, outpatients, and were in remission, in chronic treatment with typical antipsychotic and atypical antipsychotic agents. 50 healthy volunteer controls, 48 relatives with mood disorders, and 41 relatives without mental disorders were also studied. The Ethics Research Committee of Londrina State University approved the research. The patients, volunteers, and relatives were interviewed by structured diagnostic criteria, categorized according to the criteria of the fourth edition of the American Psychiatric Association’s Diagnostic and 0920-9964/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2006.02.003
Statistical Manual of Mental Disorders or DSM-IV, Axis I (SCID-IV), translated into Portuguese by Del Bem et al. (2001). Anti-hippocampus IgG was measured by enzymelinked immunosorbent assay (ELISA), using antigen from human hippocampus. Serum interleukin-6 (IL-6) was measured by chemoluminescent immunoenzymatic assay methods (ImmuliteR IL-6, Diagnostic Products Corporation, Los Angeles, CA, USA), with values of 0–5.4pg/mL. No significant difference in age was found between the four groups of subjects ( F = 0.19, df = 3, p = 0.900). The four groups did not differ significantly from each other with respect to gender (v 2 = 7.52, df = 3, p = 0.057). The groups were significantly different concerning educational background, occupational impairment, and marital status. Patients were significantly lower in educational level than controls and relatives (v 2 = 13.3, df = 3, p = 0.004). Most patients were unmarried (v 2 = 16.3, df = 3, p b 0.001), in contrast to controls and relatives. Occupational impairment was significantly higher in patients than in controls and relatives (v 2 = 133.2, df = 3, p b 0.001). The illness mean duration was 15.3 F 9.9years, and the median age of onset was 22.4 F 7.4 years. A higher percentage of patients had suicide attempts than controls, relatives without psychiatric disease, and relatives with humor disorder ( p b 0.001, Fisher’s exact test). Psychiatry hospitalizations were higher in patients than in controls, relatives without psychiatric disease, and relatives with humor disorder ( p b 0.001, Fisher’s exact test). Data showed no significant differences between groups concerning body mass index (BMI in kg/m2) ( F = 2.4, df = 3, p = 0.071, ANOVA).
Letter to the Editors
181
Table 1 Levels of interleukin-6 and antibodies against hippocampus in patients, relatives with mood disorder, relatives without mental disorder, and controls Variables
IL-6 Autoantibodies against hippocampus
Patients (n = 50)
Controls (n = 48)
Relatives without mental disorder (n = 41)
Relatives with mood disorder (n = 48)
Analysis
Median (range)
Median (range)
Median (range)
Median (range)
H
df
p
33.0a (4.9–1145) 0.147 (0.05–0.7)
5.0 (4.9–276) 0.135 (0.07–0.26)
27.3 (8.3–133) 0.144 (0.07–0.59)
54.5a (5.0–320) 0.152 (0.06–0.36)
11.78 2.16
3 3
0.008 0.540
H = Kruskal–Wallis test; df = degree of freedom. Autoantibodies = OD 492nm; IL-6 = 0–5.4pg/mL. a Dunn’s Test (significantly higher than in relatives without mental disorder and controls).
There were no statistically significant differences between groups in albumin ( F = 0.57, df = 3, p =0.637, ANOVA). Patients and relatives had higher, but not significantly, autoantibodies against hippocampus than controls (H = 2, 16, df = 3, p = 0.540, Kruskal–Wallis test) (Table 1). IL-6 was significantly higher in patients and relatives with mood disorder than in relatives without mental disorder and controls (H = 11.78, df = 3, p = 0.008, Kruskal–Wallis test followed by Dunn) (Table 1). The increased seric levels of IL-6, a pro-inflammatory cytokine, was observed in schizophrenic patients at a higher rate compared to controls in concordance with literature data (Lin et al., 1998; Rothermundt et al., 2001; Maes et al., 2000, 2002). IL-6 alterations may also occur in patients with schizophrenia, schizoaffective disorder with an unfavorable course of the disorder, longer duration of illness, treatment resistance, or more marked paranoid–hallucinatory symptomatology (Mu¨ller et al., 2000), rendering the importance of investigating it as one of the possible indicators that could be helpful in determining the evolution of the disease. In this study, it has been demonstrated that patients were chronically ill (duration of disorder 15.3 years), had early disorder onset (22.4 years), had more suicide attempts, more hospitalizations, worse occupational history, higher frequency of being unmarried, and those with lower educational background years had the poorest prognosis who were chronically ill. However, the possible involvement of an immunological or an inflammatory process in schizophrenics and their first-degree relatives with humor
disorder could be explained by genetic origin, which might be associated with viral infection/viral reactivation or to an autoimmune process. In that sense, the higher frequency of HLA.B415 was observed in these patients and relatives with and without mental disorders than in controls (Nunes et al., 2005). The findings suggest the existence of some involvement of an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives. References Del Bem, C., Vilela, J., Crippa, J., Labate, C., Zuardi, A., 2001. Confiabilidade da bentrevistaclı´nica estruturada para o D.S.M.IVQ. Rev. Bras. Psiquiatr. 23, 156 – 159 (Versa˜o clı´nica traduzida para o portugueˆs). Lin, A., Kenis, G., Bignotti, S., Tura, G., De Jong, R., Bosmans, E., Pioli, R., Altamura, C., Scharpe´, S., Maes, M., 1998. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr. Res. 32, 9 – 15. Maes, M., Chiavetto, L., Bignotti, S., Tura, G., Pioli, R., Boin, F., et al., 2000. Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur. Neuropsychopharmacol. 10, 119 – 124. Maes, M., Chiavetto, L., Bignotti, S., Tura, G., Pioli, R., Boin, F., et al., 2002. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr. Res. 54, 281 – 291. Mu¨ller, N., Riedel, M., Ackenheil, M., Schwarz, M., 2000. Cellular and humoral immune system in schizophrenia: a conceptual reevaluation. World J. Biol. Psychiatr. 1, 173 – 179. Nunes, S.O.V., Borelli, S., Matsuo T., Watanabe, M.A, Itano, E.N., 2005. The association of the HLA in patients with schizophrenia, schizoaffective disorder, and their biological relatives. Schizophrenia Research;{s.l.}.76: (.2/3), 195–198
182
Letter to the Editors
Rothermundt, M., Arolt, V., Bayer, T., 2001. Review of immunological and immunopathological findings in schizophrenia. Brain Behav. Immunol. 15, 319 – 339. Schwarz, M., Mu¨ller, N., Riedel, M., Ackenheil, M., 2001. The Th2-hypothesis of schizophrenia: a strategy to identify a subgroup of schizophrenia caused by immune mechanisms. Med. Hypotheses 56, 483 – 486.
Sandra O.V. Nunes Department of Psychiatry – Londrina State University (UEL), Brazil Corresponding author. Universidade Estadual de Londrina, Av. Adhemar de Barros, n8 625, 86050-190 – Londrina – Parana´ – Brazil. Tel.: +55 43 33390404; fax: +55 43 33238210. E-mail address: [email protected].
Tiemi Matsuo Department of Statistics and Applied Mathematics (UEL), Brazil Mari S. Kaminami Maria Ange´lica E. Watanabe Edna Maria V. Reiche Eiko N. Itano Department of Pathology, Clinical Analysis and Toxicology, Brazil 22 November 2005