BIOL PSYCHIATRY 1990;27:747-756
747
Factors Related to the Presence of Autoantibodies in Patients with Chronic Mental Disorders Stavroula G. Yannitsi, Menelaus N. Manoussakis, Anestis K. Mavridis, Athanasios G. Tzioufas, Sotirios B. Loukas, George K. Plataris, Ads D. Liakos, and Haralampos M. Moutsopoulos
Serum samples front 307 patients with various chronic mental disorders were examined for the presence of several autoantibodies. Autoantibodies detected included antinuclear antibodies (ANA) in 1221307 (39.7%), rheumatoid factor (RF) in 231307 (7.5%), anticardiolipin antibodies (anti-CL) in 231304 (7.6%, lgM in 12 patients, lgG in 13 patients). Isolated cases with lgG anti-dsDNA, anti-Ro(SSA), and anti-Ro(SSA)lanti-La(SSB) were also identified. The analysis of data revealed that the aging process in patients studied contributed significantly to the incidence of ANA (p < 0.0001) and RF (p < 0.01). In addition, the chronic administration of chlorpromazine (CPZ) was associated with the presence of ANA (p < 0.03) as well as with the presence of lgM and/or lgG anti-CL antibodies (p < 0.003). Finally, the diagnosis of schizophrenia correlated with the presence of ANA (p < 0.001). This study represents the autoantibody profile of patients with chronic mental disorders and emphasizes the multifactorial origin of autoantibody response in psychiatricpatients.
Introduction Although the presence of autoantibodies primarily characterizes the preseL:e of autoimmune diseases, several studies have indicated that patients with cl~:onic mental disorders frequently display autoantibodies such as antinuclear antibodies, anti-DNA, and lupus anticoagulant. The administration of certain psychotropic drugs, mainly chlorpromazine (CPZ) and lithium (Berglund et al. 1970; Gottfries and Gottfries 1971; Quismorio et al. 1975; presley et al. 1976; plantey 1978; Canoso and Sise 1982; Canoso et al. 1982; Zarrabi et al. 1979), as well as the nature of mental disorder (Deherdt et al. 1976; Von Brauchitsch 1972; DeLisi and Wyatt 1982; Cohen and Eisdorfer 1980) have been implicated in the induction of autoantibody response in psychiatric patients.
From the Departmentsof Psychiatry (S.G.Y., G.K.P., A.D.L.) and Internal Medicine(M.N.M., A.K.M., A.G.T., H.M.M.), School of Medicine and the Division of Statistics (S.B.L.), School of Mathematics, University of loannina, Greece. Address reprint requests to Dr. Stavroula Yannitsi, Assistant Professor of Psychiatry, Department of Psychiatry, Medical School, University of loannina, 453 32 Ioannina, Greece. Received December 22, 1988; revised July 4, 1989.
© 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
748
BIOL PSYCHIATRY 1990;27:747-756
S.G. Yannitsi et al.
During recent years, anticardiolipin (anti-CL) and other antiphospholipid antibodies, detected by either phospholipid-dependent coagulation tests (lupus-anticoagulant) or directly by solid phase assays, have been receiving increased attention. This current interest in anti-CL antibodies is due to their potential clinical significance, indicated by the reported association with thrombotic events in patients with autoimmune disorders (Harris et al. 1983; Harris et al. 1985; Derksen and Kater 1985). However, several studies have subsequently demonstrated that antiphospholipid antibodies can also be frequently detected not only in autoimmune patients but also in healthy elderly individuals as well as in patients with schizophrenia, in the absence of any associated clinical features (Canoso and Sise 1982; Gharavi et al. 1986; Manoussalds et al. 1987a; Manoussakis et al. 1987b; Sturfelt et al. 1987). In fact, the presence of antiphospholipid antibodies (illustrated by lupus-anticoagulant) in patients with schizophrenia has been attributed to chronic administration of chlorpromazine (Canoso and Sise 1982; Zarrabi et al. 1979; Canoso et al. 1977). In the present study, we examined the autoantibody profiles of a fairly l~ge number of patientg with various chronic mental disorders, and attempted to evaluate the influence of medications, psychiatric disease, as well as of gender and age in the induction of autoantibodies in psychiatric patients.
Methods Patients Included in this study were 307 patients with various chronic mental disorders (184 men and 123 women), hospitalized at the Corfu Psychiatric Hospital, Corfu, Greece. Their mean age was 55.1 +_ 14.2 years (range 22-86), their mean disease duration was 28.7 _+ 12.7 years (range 1-66), and the duration of hospitalization was 16.6 _+ 12.9 years (range 2.5 months to 54.7 years). All patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM, 3rd Edition, American Psychiatric Association), using psychiatric interview and patients' records. Patients' diagnoses included schizophrenic disorders (179 patients), psychotic disorders not elsewhere classified (20), major affective disorders (14), borderline personality disorders (6), alcohol dependence (6), organic brain syndromes (18), and mental retardation (64).
Treatment Most patients had been under treatment with neuroleptic and various other drags for several years. Drug cegimens included phenothiazines (CPZ, other phenothiazines), nonphenothiazine neuroleptics (haloperidol, other neuroleptics), antidepressants, benzodiazepines, lithium carbonate, antiparldnsonian-anticholinergic drugs, beta-blockers, and diuretics. Patients were classified into various subgroups according to their drug treatment.
Serological Studies Coded serum samples were stored at -30°C until testing. Studies included examinations for the presence of antinuclear antibodies (ANA) (by indirect immunofluorescenee technique using Hep-2 cells, positive titer ~> 1:80); antibodies to Ro(SSA), La(SSB), U~nRNP~
Autoantibodies in Chronic Mental Disorder
BIOL PSYCHIATRY 1990;27:747-756
749
and Sm cellular antigens (by double immunodiffusion and counterimmunoelectrophoresis using human spleen and calf thymus extracts); rheumatoid factor (RF) (by latex-fixation test, positive titer ~ 1:40). In addition, the presence and levels of IgG antibodies to double-stranded DNA (anti-dsDNA) in 307 sera, and of IgM and IgG antibodies to cardiolipin (anti-CL) in 304 sera, were determined by quantitative isotype-specific enzyme-immunosorbent assays (ELISA) as previously described (Manoussalds et -,~. I987a; Manoussakis et al. 1987b; Tzioufas et al. 1987). According to these ELISA methods, results were expressed as binding index (BI), with BI of 100 being defined as the cutoff point for positivity (4 standard deviations above the mean of 267 healthy blood donors previously examined). All autoantibodies under study have been originally demonstrated in various autoimmune diseases. Antibodies to extracted cellular antigens (ribonucleoproteins) such as antibodies to Ro(SSA) and La(SSB) antigens (initially foun0 in Sj6gren's syndrome, i.e., Sj6gren's syndrome antigens A and B) are known to prevail in Sj6~en's syndrome as well as in systemic lupus erythematosus (SLE). Autoantibodies to U~ nuclear ribonucleoprotein (U~nRNP) are usually encountered in mixed connective tissue disease as well as in SLE, whereas anti-Sm antibodies (Smith antigen) as well as anti-dsDNA antibodies are specifically observed in SLE. Finally, anticardiolipin antibodies, although originally demonstrated in SLE, in subsequent studies have also been shown in several autoimmune disorders.
Controls The serological findings from 150 serum samples from healthy blood donors (82 women and 68 men, mean age 53.1 _ 17.2 years with age ranging from 20 to 85 years) served as controls.
Statistical Analysis Data were analyzed by Student's t-test, chi-square test with Yates' correction, and linear regression analysis, where applicable. In statistical analysis, the mean age of 55 years was used to divide patients into two age groups (~55 and >55 years). In addition, we used the multiple logistic regression model which is appropriate in examining the relations of a number of independent categorical variables (gender, diagnosis, treatment groups) or continuous ones (age, disease duration) in interaction with a binary dependent variable (a serologic parameter, e.g., ANA + , ANA - ) . The multiple logistic regression analysis was performed by the program LR of the BMDP statistical package.
Results The serological profile of patients and healthy controls studied is shown in Table 1. Autoantibodies in healthy controls were observed only in individuals ~55 years (total 65) including RF in 7 (10.8%), ANA in 10 (15.4%), anti-Ro(SSA) in 1 (1.5%), antidsDNA in 2 (3.1%), and anticardiolipin in 9 (12.3%). Positive ANA tests were observed in 122 patients (39.7%) and RF was detected in 23 patients (7.5%). Fifteen patients displayed both positive ANA and RF tests. Positive ANA titers ranged from 1:80 to 1:2560 (mean positive ANA tiler 1:124), and positive RF titers ranged from 1:40 to 1:640 (mean positive RF titer 1:137). Highly positive titers
750
S.G. Yannitsi et al.
BIOL PSYCHIATRY 1990;27:747-756
Table 1. Prevalence of Autoantibodies Studied in Patients with Chronic Mental Disorders and Healthy Controls % Positive
RF ANA Anti-Ro(SSA) Anti-La(SSB) Anti-dsDNA Anti-CL
Patients (n = 307)
Controls (n = 150)
7.5 39.7° 0.7 0.3 0.3 7.6 b
4.7 6.7 0,7 0,0 1.3 6.0
Op< 0.001. b~n23 of 304 patients studied.
(>~1:320) of ANA and RF were observed in 7 and 3 patients, respectively. Antibodies to Ro(SSA) were detected in 2 patients (women, 65 and 69 years, respectively); in 1 of them, together with anti-La(SSA) antibodies. Finally, anti-dsDNA antibodies were found in only 1 patient (a man with schizophrenia, aged 74, BI = 314). As shown in Table 2, the analysis of the data revealed a highly significant preponderance of positive ANA tests among patients with age >55 years compared with those 55 years (p < 0.01). Among drugs, CPZ was the only drug whose administration tended to associate with ANA positivity (Table 2). It is evident (Table 2) that among the various associations of positive ANA tests observed, the association with age showed the greatest significance. Thus, we attempted to evaluate whether the aging process in this psychiatric population was a factor in the high prevalence of ANA observed in female patients, in patients with schizophrenia, and
Table 2. Prevalence of Positive ANA and RF Tests in Subgroups of Patients According to Age, Gender, Diagnosis of Schizophrenia, and Chlorpromazine Treatment ANA Positive (~) Age ~55 years (n = 147) Age >55 years (n - 160) Men (n - 184) Women (n -- 123) Nonschizophrenia (n = 128) Schizophrenia (n = 179) No chlorpromazine (n = 260) Chlorpromazine (n -- 47) NS = nonsignificant
27.9 50.6 33.7 48.8 28.1 48.1 37,7 51.1
RF Significance (p)
747
Factors Related to the Presence of Autoantibodies in Patients with Chronic Mental Disorders Stavroula G. Yannitsi, Menelaus N. Manoussakis, Anestis K. Mavridis, Athanasios G. Tzioufas, Sotirios B. Loukas, George K. Plataris, Ads D. Liakos, and Haralampos M. Moutsopoulos
Serum samples front 307 patients with various chronic mental disorders were examined for the presence of several autoantibodies. Autoantibodies detected included antinuclear antibodies (ANA) in 1221307 (39.7%), rheumatoid factor (RF) in 231307 (7.5%), anticardiolipin antibodies (anti-CL) in 231304 (7.6%, lgM in 12 patients, lgG in 13 patients). Isolated cases with lgG anti-dsDNA, anti-Ro(SSA), and anti-Ro(SSA)lanti-La(SSB) were also identified. The analysis of data revealed that the aging process in patients studied contributed significantly to the incidence of ANA (p < 0.0001) and RF (p < 0.01). In addition, the chronic administration of chlorpromazine (CPZ) was associated with the presence of ANA (p < 0.03) as well as with the presence of lgM and/or lgG anti-CL antibodies (p < 0.003). Finally, the diagnosis of schizophrenia correlated with the presence of ANA (p < 0.001). This study represents the autoantibody profile of patients with chronic mental disorders and emphasizes the multifactorial origin of autoantibody response in psychiatricpatients.
Introduction Although the presence of autoantibodies primarily characterizes the preseL:e of autoimmune diseases, several studies have indicated that patients with cl~:onic mental disorders frequently display autoantibodies such as antinuclear antibodies, anti-DNA, and lupus anticoagulant. The administration of certain psychotropic drugs, mainly chlorpromazine (CPZ) and lithium (Berglund et al. 1970; Gottfries and Gottfries 1971; Quismorio et al. 1975; presley et al. 1976; plantey 1978; Canoso and Sise 1982; Canoso et al. 1982; Zarrabi et al. 1979), as well as the nature of mental disorder (Deherdt et al. 1976; Von Brauchitsch 1972; DeLisi and Wyatt 1982; Cohen and Eisdorfer 1980) have been implicated in the induction of autoantibody response in psychiatric patients.
From the Departmentsof Psychiatry (S.G.Y., G.K.P., A.D.L.) and Internal Medicine(M.N.M., A.K.M., A.G.T., H.M.M.), School of Medicine and the Division of Statistics (S.B.L.), School of Mathematics, University of loannina, Greece. Address reprint requests to Dr. Stavroula Yannitsi, Assistant Professor of Psychiatry, Department of Psychiatry, Medical School, University of loannina, 453 32 Ioannina, Greece. Received December 22, 1988; revised July 4, 1989.
© 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
748
BIOL PSYCHIATRY 1990;27:747-756
S.G. Yannitsi et al.
During recent years, anticardiolipin (anti-CL) and other antiphospholipid antibodies, detected by either phospholipid-dependent coagulation tests (lupus-anticoagulant) or directly by solid phase assays, have been receiving increased attention. This current interest in anti-CL antibodies is due to their potential clinical significance, indicated by the reported association with thrombotic events in patients with autoimmune disorders (Harris et al. 1983; Harris et al. 1985; Derksen and Kater 1985). However, several studies have subsequently demonstrated that antiphospholipid antibodies can also be frequently detected not only in autoimmune patients but also in healthy elderly individuals as well as in patients with schizophrenia, in the absence of any associated clinical features (Canoso and Sise 1982; Gharavi et al. 1986; Manoussalds et al. 1987a; Manoussakis et al. 1987b; Sturfelt et al. 1987). In fact, the presence of antiphospholipid antibodies (illustrated by lupus-anticoagulant) in patients with schizophrenia has been attributed to chronic administration of chlorpromazine (Canoso and Sise 1982; Zarrabi et al. 1979; Canoso et al. 1977). In the present study, we examined the autoantibody profiles of a fairly l~ge number of patientg with various chronic mental disorders, and attempted to evaluate the influence of medications, psychiatric disease, as well as of gender and age in the induction of autoantibodies in psychiatric patients.
Methods Patients Included in this study were 307 patients with various chronic mental disorders (184 men and 123 women), hospitalized at the Corfu Psychiatric Hospital, Corfu, Greece. Their mean age was 55.1 +_ 14.2 years (range 22-86), their mean disease duration was 28.7 _+ 12.7 years (range 1-66), and the duration of hospitalization was 16.6 _+ 12.9 years (range 2.5 months to 54.7 years). All patients were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM, 3rd Edition, American Psychiatric Association), using psychiatric interview and patients' records. Patients' diagnoses included schizophrenic disorders (179 patients), psychotic disorders not elsewhere classified (20), major affective disorders (14), borderline personality disorders (6), alcohol dependence (6), organic brain syndromes (18), and mental retardation (64).
Treatment Most patients had been under treatment with neuroleptic and various other drags for several years. Drug cegimens included phenothiazines (CPZ, other phenothiazines), nonphenothiazine neuroleptics (haloperidol, other neuroleptics), antidepressants, benzodiazepines, lithium carbonate, antiparldnsonian-anticholinergic drugs, beta-blockers, and diuretics. Patients were classified into various subgroups according to their drug treatment.
Serological Studies Coded serum samples were stored at -30°C until testing. Studies included examinations for the presence of antinuclear antibodies (ANA) (by indirect immunofluorescenee technique using Hep-2 cells, positive titer ~> 1:80); antibodies to Ro(SSA), La(SSB), U~nRNP~
Autoantibodies in Chronic Mental Disorder
BIOL PSYCHIATRY 1990;27:747-756
749
and Sm cellular antigens (by double immunodiffusion and counterimmunoelectrophoresis using human spleen and calf thymus extracts); rheumatoid factor (RF) (by latex-fixation test, positive titer ~ 1:40). In addition, the presence and levels of IgG antibodies to double-stranded DNA (anti-dsDNA) in 307 sera, and of IgM and IgG antibodies to cardiolipin (anti-CL) in 304 sera, were determined by quantitative isotype-specific enzyme-immunosorbent assays (ELISA) as previously described (Manoussalds et -,~. I987a; Manoussakis et al. 1987b; Tzioufas et al. 1987). According to these ELISA methods, results were expressed as binding index (BI), with BI of 100 being defined as the cutoff point for positivity (4 standard deviations above the mean of 267 healthy blood donors previously examined). All autoantibodies under study have been originally demonstrated in various autoimmune diseases. Antibodies to extracted cellular antigens (ribonucleoproteins) such as antibodies to Ro(SSA) and La(SSB) antigens (initially foun0 in Sj6gren's syndrome, i.e., Sj6gren's syndrome antigens A and B) are known to prevail in Sj6~en's syndrome as well as in systemic lupus erythematosus (SLE). Autoantibodies to U~ nuclear ribonucleoprotein (U~nRNP) are usually encountered in mixed connective tissue disease as well as in SLE, whereas anti-Sm antibodies (Smith antigen) as well as anti-dsDNA antibodies are specifically observed in SLE. Finally, anticardiolipin antibodies, although originally demonstrated in SLE, in subsequent studies have also been shown in several autoimmune disorders.
Controls The serological findings from 150 serum samples from healthy blood donors (82 women and 68 men, mean age 53.1 _ 17.2 years with age ranging from 20 to 85 years) served as controls.
Statistical Analysis Data were analyzed by Student's t-test, chi-square test with Yates' correction, and linear regression analysis, where applicable. In statistical analysis, the mean age of 55 years was used to divide patients into two age groups (~55 and >55 years). In addition, we used the multiple logistic regression model which is appropriate in examining the relations of a number of independent categorical variables (gender, diagnosis, treatment groups) or continuous ones (age, disease duration) in interaction with a binary dependent variable (a serologic parameter, e.g., ANA + , ANA - ) . The multiple logistic regression analysis was performed by the program LR of the BMDP statistical package.
Results The serological profile of patients and healthy controls studied is shown in Table 1. Autoantibodies in healthy controls were observed only in individuals ~55 years (total 65) including RF in 7 (10.8%), ANA in 10 (15.4%), anti-Ro(SSA) in 1 (1.5%), antidsDNA in 2 (3.1%), and anticardiolipin in 9 (12.3%). Positive ANA tests were observed in 122 patients (39.7%) and RF was detected in 23 patients (7.5%). Fifteen patients displayed both positive ANA and RF tests. Positive ANA titers ranged from 1:80 to 1:2560 (mean positive ANA tiler 1:124), and positive RF titers ranged from 1:40 to 1:640 (mean positive RF titer 1:137). Highly positive titers
750
S.G. Yannitsi et al.
BIOL PSYCHIATRY 1990;27:747-756
Table 1. Prevalence of Autoantibodies Studied in Patients with Chronic Mental Disorders and Healthy Controls % Positive
RF ANA Anti-Ro(SSA) Anti-La(SSB) Anti-dsDNA Anti-CL
Patients (n = 307)
Controls (n = 150)
7.5 39.7° 0.7 0.3 0.3 7.6 b
4.7 6.7 0,7 0,0 1.3 6.0
Op< 0.001. b~n23 of 304 patients studied.
(>~1:320) of ANA and RF were observed in 7 and 3 patients, respectively. Antibodies to Ro(SSA) were detected in 2 patients (women, 65 and 69 years, respectively); in 1 of them, together with anti-La(SSA) antibodies. Finally, anti-dsDNA antibodies were found in only 1 patient (a man with schizophrenia, aged 74, BI = 314). As shown in Table 2, the analysis of the data revealed a highly significant preponderance of positive ANA tests among patients with age >55 years compared with those 55 years (p < 0.01). Among drugs, CPZ was the only drug whose administration tended to associate with ANA positivity (Table 2). It is evident (Table 2) that among the various associations of positive ANA tests observed, the association with age showed the greatest significance. Thus, we attempted to evaluate whether the aging process in this psychiatric population was a factor in the high prevalence of ANA observed in female patients, in patients with schizophrenia, and
Table 2. Prevalence of Positive ANA and RF Tests in Subgroups of Patients According to Age, Gender, Diagnosis of Schizophrenia, and Chlorpromazine Treatment ANA Positive (~) Age ~55 years (n = 147) Age >55 years (n - 160) Men (n - 184) Women (n -- 123) Nonschizophrenia (n = 128) Schizophrenia (n = 179) No chlorpromazine (n = 260) Chlorpromazine (n -- 47) NS = nonsignificant
27.9 50.6 33.7 48.8 28.1 48.1 37,7 51.1
RF Significance (p)
