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Antinuclear and gastric parietal cell autoantibodies in schizophrenic patients
BIOL PSYCHIATRY 1992132:735-738
735
Antinuclear and Gastric Parietal Cell Autoantibodies in Schizophrenic Patients Rohan Ganguli, Bruce S. Rabin, and Jaspreet S. Brar
Introduction
Methods
There are two approaches to determine whether a disease has an autoimmune pathology (Rose 1991). The direct approach, as exemplified by myasthenia gravis and Graves' disease, is the detection of antigen-specific autoantibodies with pathophysiological significance (Roitt et al 1989). However, in most diseases such as systemic lur:~ ythematosus (SLE), rheumatoid artiwitis, and multiple sclerosis there is only indirect evidence of autoimmunity. This indirect evidence is provided by (1), the occurrence of other autoimmune disorders in other family members, (2), non-organ specific autoantibodies such as antinuclear antibody (ANA) which may covary with exacerbations and remissions of illness, and (3) altered lymphokine production (Kroe. mer et al 1991). If some schizophrenics have an autoimmune disease as suggested by us (Ganguli et al 1987, 1989) and others, then an increased prevalence of autoantibodies in association with the disorder would be predicted. In this study, we report our findings on the prevalence of seven common circulating autoantibodies in schizophrenic patients (including first-episode, neuroleptic-naive patients) and healthy control subjects.
Clinical Patients (n = 225; 125 men, 100 women) who met the Research Diagnostic Criteria (Spitzer et al 1978a) for Schizophrenia or Schizo-Affective disorder (mainly schizophrenic), based on a modified Schedule for Affective Disorder and Schizophrenia (Spitzer et al 1978b) interview were recruited from the Western Psychiatric Institute and Clinic, Pittsburgh, PA. The diagnosis in first-episode patients (n = 53) was reconfirmed 9-12 months later as described elsewhere (Ganguli and Brat 1992). Positive and negative symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and the Manchester Scale (Kraweicka 1977). Depression was rated using the Montgomery-Asberg scale (Montgomery and Asberg 1979). Control subjects (n = 327; 141 men, 186 women) from the Pittsburgh metropolitan area were recruited for this study, and excluded if they had any mental disorder, immune disorder, current drug or alcohol abuse, or addiction. Fifty-three age-, race-, and gendermatched controls were selected from this sample for comparison with the first-episode patients.
Immunologic From the Departments of Psychiatry and Pathology, Immunopsychiatry Programme and Immunopathology Division, University of Pittsburgh School of Medicine and Brain Behaviour and Immunity Center, Pittsburgh, PA. Address reprint requests to Rohan Ganguli, M.D.. Western Psychiatric Institute & Clinic, 3811 O'Hara Street, Pittsburgh, PA ! 5213-2593. Received March 11, 1992; revised July 8, 1992.
© 1992 Society of Biological Psychiatry
Sera was tested for seven common autoantibodies using standard serological methods: thyroglobulin and thyroid microsomal agent by indirect hemagglutination; immunofluorescence for antinuclear antibody (HEp-2 cell line), smooth 0006-3223/92/$05.00
736
BIOLPSYCHIATRY
Brief Reports
1992;32:735-738
muscle, mitochondria, and gastric parietal cell (mouse stomach and kidney); rheumatoid factor by fluorescence immunoassay. Subjects were considered positive if the titer of any one or more of the autoantibodies exceeded the threshold established by the clinical serology laboratory of this university hospital.
cated and previously medicated), lower BPRS and negative symptoms scores were found in the ANA-positive group (see Table 2). Discussion
Our findings confirm an increased prevalence of autoantibodies in schizophrenic patients (Fessel 1961; DeLisi and Wyatt 1982; Canoso et al 1990); Results however, this increase does not appear to be a The prevalence of autoantibodies in these two generalized increase in all common autoantipopulations was compared using Pearson's X2 bodies as we first hypothesized but to be specific and Fisher's exact tests (Table 1). Notable were to ANA and to a lesser extent gastric parietal the differences in the prevalence of ANA (Bon- cell antibody. Based on the earlier work with ferroni corrected p ffi 0.047) between the two chlorpromazine (Berglund et al 1970; Quispopulations. Furthermore, ANA was twice as morio et al 1975; Alarcon-Segovia et al 1973; frequent in female patients than in males (X2 = Zarrabi et al 1979; Gammon et al 1980; Yannitsi 5.92, p = 0.012). Although gastric parietal cell et al 1990), the increase in ANA in schizoantibodies were also twice as frequent among phrenics might be suspected to be due to medpatients compared with controls, the diffi:rence ications, and this can still not be ruled out. By failed to reach statistical significance. Eight of including the largest sample of never-medicated the 10 patients that were positive for gastric patients so far studied, we had hoped to deterparietal cell antibodies were African-American mine if increased ANA was related to medications. There was no statistically significant dif(Fisher's exact, 2-tailed p -- 0.046). ANA was positive in 9.43% of never-med- ference between never-medicated patients and icated patients compared with 5.66% in age-, age-, race-, and gender-matched controls. Howrace-, and gender-matched controls, but the dif- ever, this may be an issue of statistical power as it would take 593 never-medicated patients ferences were not statistically significant. There was a significant linear association be- and an equal number of controls for the observed tween ANA positivity and age in patients (exact difference to reach statistical signficance (power p - 0,0001; Armitage 1955). A similar trend = 0.80; I tailed ¢t set at 0.05). Earlier studies was also found with duration of illness. of never-medicated patients have reported an Among all acutely ill patients (never-medi- increase in ANA (DeLisi and Wyatt 1982) and
Table I. Prevalenceof Autoantibodies in SchizophrenicPatients and Healthy Controls Autoantibody
Patient" (225) (%)
Controls (327) (%)
ANA Smooth muscle Gastric parietal cell Mitochondrial Thyroglc~n Thyroid n,crosomal" Rheumatoid factor Sum 7
30 (13.33) 23 (10.22) 10 (4.44) I (0.44) 7 (3,11) 15 (6,67) 7 (3. I I) 69 (29.78)
20 30 7 2 13 25 10 ~
°Includes53 first episode, drug-naivepatients.
(6,12) (9,17) (2,14) (0,61) (3,98) (7,65) (3,06) (27.5)
X2
p (<)
7.57 0.07 !,66 Fisher's exact 0.10 0.09 0.05 0.41
0.0059 ns ns ns ns ns ns ns
Brief Reports
BIOLPSYCHIATRY
737
1992;32:735-738
Table 2. Relationship of Clinical Scores to ANA Status in Acutely I!i Schizophrenic Patients (NeverMedicated and Previously Medicated) Clinical ratings BPRS score Negative symptoms score Depression score
ANA status
Me~..q ± SD
+re -ve +ve -ve + ve -ve
47.29 62.05 1.71 3.86 3.14 4.29
_+ It.15 • 15.65 -4. 2.63 -- 4.43 ± 2.61 _ 3.81
/~ 0.011 0.077 ns
Sample comprised of 14 ANA positive, and 118 ANA negativepatients. "Significancevalues based on Mann-WhitneyU statistics.
anticardiolipin antibodies (Chengappa et al 1991) in this population. Sirota et al (1991) found increased prevalence of ANA antibodies in the unmedicated well relatives of schizophrenic probands, suggesting that these antibodies are not the consequences of treatment. Could our ANA-positive patients be suffering from undiagnosed SLE? This cannot be ruled out but seems unlikely in view of the fact that many of these patients had been ill for many years without showing any skin, joint, or other signs of lupus. We have no satisfactory explanation yet for why there was a significantly higher prevalence of gastric parietal cell antibody in black subjects compared with white subjects. Racial differences between blacks and whites for some immunologic parameters such as lymp'nokine production (Ganguli and Rabin 19Y39) and susceptibility to mycobacterial infection (Stead et al 1990) have been reported. The issue of the rate of pernicious anemia and atrophic gastritis (diseases associated with gastric parietal cell antibodies) in blacks has not been studied as far as we know. In conclusion, some, but not all autoantibodies are found with a higher frequency in schizophrenic patients, and the prevalence of these autoantibodies increases with age. These autoantibodies, namely, ANA and gastric parietal cell antibody, could be used to segregate a subgroup of schizophrenics who may t.ave an autoimmune component to the pathogenesis of their illness.
The studies reported here were partially supported by the following grants: NIMH RO! MH41883, NIMH KOI (Research Scientist Development Award) MH00710, and a NARSAD Established Investigator Award. The authors wish to acknowledge the assistance of the following individuals in the conduct of studies reported here: Marcia DeLeo, Ellen Hammill, Alisa Mazzrella, Rosemarie Perla, Wendy Solomon, and Ann Wu.
References Alarcon-Segovia D, Fishbein E, Cetina JA, Raya RJ, Berrera E (1973): Antigenic specificity of chlorpromazine-induced antinuclear antibodies. Clin Exp Immunol 15(4): 543-548. Armitage P (1955): Test for linear trend in proportions and frequencies. Biometrics II :375-386. Berglund S, Gottfries CG, Gottfries I, Stormby K (1970): Chlorpromazine-induced antinuclear factors.Acta Med $cand 187(I-2): 67-74. Canoso RT, de OliveiraRM, Nixon RA (1990): Neuroleptic-associatedautoantibodies. A prevalence study. Biol Psychiatry27:863-870. Chengappa KNR, Carpenter AB, Keshavan MS, et al (1991): Elevated IgG and IgM anti-cardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients. Biol Psychiatry 30:731-735. DeLisi LE, Wyatt RJ (1982): At,aormal immune regulation in schizophrenic patients. Psychopharmacol Bull 18:158-163. Fessel WI (1961): Disturbed serum proteins in chronic psychosis. Arch Gun Psychiatry 4: i 54-159. Gammon GD, Hafez H, Docherty JP (1980): Chlorpromazine and immunologic considerations of schizophrenia. Ann Intern Mud 92:441.-.442. Ganguli R, Rabin BS (1989): Differences in inter-
738
BIOLPSYCHIATRY 1992;32:735-738
leukin-2 production in blacks and whites. N Engl J Med 320--399. Ganguli R, Brar JS (1992): Generalizability of first episode studies in schizophrenia. Schizophr Bull 18(3):436-469. Ganguli R, Rabin BS, Kelly RH, Lyre M, Raghu U (1987): Clinical and laboratory evidence of autoimmunity in acute schizophrenia. Ann NY Acad Sci 496;676-685. Ganguli R, Rabin BS, Kelly RH (1989): Multiple autoantibodiesand autoimmunedisease in schizophrenic patients: Evidence for an autoimmune pathogenesis. In Hadden JW, Masek K, Nistico (3 (eds), hlteractions Among CNS, Neuroendo. crine and bnmune Systems. Rome-Milan: Pythagora Press, 365-384. Krawcicka M, Goldberg D, Waughn N (1977): A standard psychiatric scale for rating psychotic patients. Acta Psychiatr Scand 55:299-308. Kroemer G, Andreu JL, Gonzalo JA, Gutierrez-Ra. mos JC, Martinez-AC (1991): Interleukin-2, autotolerance, and autoimmunity. Adv Immunol 50:147-235. Montgomery SA, Asberg M (1979): A new depression scale designed to be se~.~+.tiveto change. Br J Psychiatry 134:382-389. Overall JE, Gorham DR ( 1962):The Brief Psychiatric Rating Scale. Psychol Rep 10:799-812. Quismorio FP, Bjamason DF, Kiely WF, Dubois EL,
Brief Reports
Friou GJ (1975): Antinuclear antibodies in chronic psychotic patients ~reated with chlorpromazine. Am J Psychiatry 132(!!): 1204-1206. Roitt IM, Brostoff J, Male DK (eds) (1989): Immunology. New York: CV Mosby. Rose NR (1991): Characteristics of autoimmune disease. J Invest Dermatol 96:87S. Sirota P, Schild K, Firer M, et al (1991): Autoantibodies to DNA in multicase families with schizophrenia. Biol Psychiatry 29(9A): I03A. Spitzer RL, Endicott J, Robins E (1978a): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 35:773-782, Spitzer RL, Endictt J, Robins E (1978b): The Schedule for Affective Disorders and Schizophrenia (SADS). New York: New York State Psychiatric Institute. Stead WW, Senner JW, Reddick WT, Lofgrcn .IP (1990): Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engi J Med 322:422-42?. Yannitsi SO, Manoussakis MN, Mavridis AK, et al (1990): Factors related to the presence of autoantibodies in patients with chronic mental disorders. Biol Psychiatry 27:747-'/55. Zarrabi MH, Zucker S, Miller F (1979): Immunologic and coagulationdisorders in chlorpromazine-treatcd patients. Ann Intern Med 91:194-199.
735
Antinuclear and Gastric Parietal Cell Autoantibodies in Schizophrenic Patients Rohan Ganguli, Bruce S. Rabin, and Jaspreet S. Brar
Introduction
Methods
There are two approaches to determine whether a disease has an autoimmune pathology (Rose 1991). The direct approach, as exemplified by myasthenia gravis and Graves' disease, is the detection of antigen-specific autoantibodies with pathophysiological significance (Roitt et al 1989). However, in most diseases such as systemic lur:~ ythematosus (SLE), rheumatoid artiwitis, and multiple sclerosis there is only indirect evidence of autoimmunity. This indirect evidence is provided by (1), the occurrence of other autoimmune disorders in other family members, (2), non-organ specific autoantibodies such as antinuclear antibody (ANA) which may covary with exacerbations and remissions of illness, and (3) altered lymphokine production (Kroe. mer et al 1991). If some schizophrenics have an autoimmune disease as suggested by us (Ganguli et al 1987, 1989) and others, then an increased prevalence of autoantibodies in association with the disorder would be predicted. In this study, we report our findings on the prevalence of seven common circulating autoantibodies in schizophrenic patients (including first-episode, neuroleptic-naive patients) and healthy control subjects.
Clinical Patients (n = 225; 125 men, 100 women) who met the Research Diagnostic Criteria (Spitzer et al 1978a) for Schizophrenia or Schizo-Affective disorder (mainly schizophrenic), based on a modified Schedule for Affective Disorder and Schizophrenia (Spitzer et al 1978b) interview were recruited from the Western Psychiatric Institute and Clinic, Pittsburgh, PA. The diagnosis in first-episode patients (n = 53) was reconfirmed 9-12 months later as described elsewhere (Ganguli and Brat 1992). Positive and negative symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and the Manchester Scale (Kraweicka 1977). Depression was rated using the Montgomery-Asberg scale (Montgomery and Asberg 1979). Control subjects (n = 327; 141 men, 186 women) from the Pittsburgh metropolitan area were recruited for this study, and excluded if they had any mental disorder, immune disorder, current drug or alcohol abuse, or addiction. Fifty-three age-, race-, and gendermatched controls were selected from this sample for comparison with the first-episode patients.
Immunologic From the Departments of Psychiatry and Pathology, Immunopsychiatry Programme and Immunopathology Division, University of Pittsburgh School of Medicine and Brain Behaviour and Immunity Center, Pittsburgh, PA. Address reprint requests to Rohan Ganguli, M.D.. Western Psychiatric Institute & Clinic, 3811 O'Hara Street, Pittsburgh, PA ! 5213-2593. Received March 11, 1992; revised July 8, 1992.
© 1992 Society of Biological Psychiatry
Sera was tested for seven common autoantibodies using standard serological methods: thyroglobulin and thyroid microsomal agent by indirect hemagglutination; immunofluorescence for antinuclear antibody (HEp-2 cell line), smooth 0006-3223/92/$05.00
736
BIOLPSYCHIATRY
Brief Reports
1992;32:735-738
muscle, mitochondria, and gastric parietal cell (mouse stomach and kidney); rheumatoid factor by fluorescence immunoassay. Subjects were considered positive if the titer of any one or more of the autoantibodies exceeded the threshold established by the clinical serology laboratory of this university hospital.
cated and previously medicated), lower BPRS and negative symptoms scores were found in the ANA-positive group (see Table 2). Discussion
Our findings confirm an increased prevalence of autoantibodies in schizophrenic patients (Fessel 1961; DeLisi and Wyatt 1982; Canoso et al 1990); Results however, this increase does not appear to be a The prevalence of autoantibodies in these two generalized increase in all common autoantipopulations was compared using Pearson's X2 bodies as we first hypothesized but to be specific and Fisher's exact tests (Table 1). Notable were to ANA and to a lesser extent gastric parietal the differences in the prevalence of ANA (Bon- cell antibody. Based on the earlier work with ferroni corrected p ffi 0.047) between the two chlorpromazine (Berglund et al 1970; Quispopulations. Furthermore, ANA was twice as morio et al 1975; Alarcon-Segovia et al 1973; frequent in female patients than in males (X2 = Zarrabi et al 1979; Gammon et al 1980; Yannitsi 5.92, p = 0.012). Although gastric parietal cell et al 1990), the increase in ANA in schizoantibodies were also twice as frequent among phrenics might be suspected to be due to medpatients compared with controls, the diffi:rence ications, and this can still not be ruled out. By failed to reach statistical significance. Eight of including the largest sample of never-medicated the 10 patients that were positive for gastric patients so far studied, we had hoped to deterparietal cell antibodies were African-American mine if increased ANA was related to medications. There was no statistically significant dif(Fisher's exact, 2-tailed p -- 0.046). ANA was positive in 9.43% of never-med- ference between never-medicated patients and icated patients compared with 5.66% in age-, age-, race-, and gender-matched controls. Howrace-, and gender-matched controls, but the dif- ever, this may be an issue of statistical power as it would take 593 never-medicated patients ferences were not statistically significant. There was a significant linear association be- and an equal number of controls for the observed tween ANA positivity and age in patients (exact difference to reach statistical signficance (power p - 0,0001; Armitage 1955). A similar trend = 0.80; I tailed ¢t set at 0.05). Earlier studies was also found with duration of illness. of never-medicated patients have reported an Among all acutely ill patients (never-medi- increase in ANA (DeLisi and Wyatt 1982) and
Table I. Prevalenceof Autoantibodies in SchizophrenicPatients and Healthy Controls Autoantibody
Patient" (225) (%)
Controls (327) (%)
ANA Smooth muscle Gastric parietal cell Mitochondrial Thyroglc~n Thyroid n,crosomal" Rheumatoid factor Sum 7
30 (13.33) 23 (10.22) 10 (4.44) I (0.44) 7 (3,11) 15 (6,67) 7 (3. I I) 69 (29.78)
20 30 7 2 13 25 10 ~
°Includes53 first episode, drug-naivepatients.
(6,12) (9,17) (2,14) (0,61) (3,98) (7,65) (3,06) (27.5)
X2
p (<)
7.57 0.07 !,66 Fisher's exact 0.10 0.09 0.05 0.41
0.0059 ns ns ns ns ns ns ns
Brief Reports
BIOLPSYCHIATRY
737
1992;32:735-738
Table 2. Relationship of Clinical Scores to ANA Status in Acutely I!i Schizophrenic Patients (NeverMedicated and Previously Medicated) Clinical ratings BPRS score Negative symptoms score Depression score
ANA status
Me~..q ± SD
+re -ve +ve -ve + ve -ve
47.29 62.05 1.71 3.86 3.14 4.29
_+ It.15 • 15.65 -4. 2.63 -- 4.43 ± 2.61 _ 3.81
/~ 0.011 0.077 ns
Sample comprised of 14 ANA positive, and 118 ANA negativepatients. "Significancevalues based on Mann-WhitneyU statistics.
anticardiolipin antibodies (Chengappa et al 1991) in this population. Sirota et al (1991) found increased prevalence of ANA antibodies in the unmedicated well relatives of schizophrenic probands, suggesting that these antibodies are not the consequences of treatment. Could our ANA-positive patients be suffering from undiagnosed SLE? This cannot be ruled out but seems unlikely in view of the fact that many of these patients had been ill for many years without showing any skin, joint, or other signs of lupus. We have no satisfactory explanation yet for why there was a significantly higher prevalence of gastric parietal cell antibody in black subjects compared with white subjects. Racial differences between blacks and whites for some immunologic parameters such as lymp'nokine production (Ganguli and Rabin 19Y39) and susceptibility to mycobacterial infection (Stead et al 1990) have been reported. The issue of the rate of pernicious anemia and atrophic gastritis (diseases associated with gastric parietal cell antibodies) in blacks has not been studied as far as we know. In conclusion, some, but not all autoantibodies are found with a higher frequency in schizophrenic patients, and the prevalence of these autoantibodies increases with age. These autoantibodies, namely, ANA and gastric parietal cell antibody, could be used to segregate a subgroup of schizophrenics who may t.ave an autoimmune component to the pathogenesis of their illness.
The studies reported here were partially supported by the following grants: NIMH RO! MH41883, NIMH KOI (Research Scientist Development Award) MH00710, and a NARSAD Established Investigator Award. The authors wish to acknowledge the assistance of the following individuals in the conduct of studies reported here: Marcia DeLeo, Ellen Hammill, Alisa Mazzrella, Rosemarie Perla, Wendy Solomon, and Ann Wu.
References Alarcon-Segovia D, Fishbein E, Cetina JA, Raya RJ, Berrera E (1973): Antigenic specificity of chlorpromazine-induced antinuclear antibodies. Clin Exp Immunol 15(4): 543-548. Armitage P (1955): Test for linear trend in proportions and frequencies. Biometrics II :375-386. Berglund S, Gottfries CG, Gottfries I, Stormby K (1970): Chlorpromazine-induced antinuclear factors.Acta Med $cand 187(I-2): 67-74. Canoso RT, de OliveiraRM, Nixon RA (1990): Neuroleptic-associatedautoantibodies. A prevalence study. Biol Psychiatry27:863-870. Chengappa KNR, Carpenter AB, Keshavan MS, et al (1991): Elevated IgG and IgM anti-cardiolipin antibodies in a subgroup of medicated and unmedicated schizophrenic patients. Biol Psychiatry 30:731-735. DeLisi LE, Wyatt RJ (1982): At,aormal immune regulation in schizophrenic patients. Psychopharmacol Bull 18:158-163. Fessel WI (1961): Disturbed serum proteins in chronic psychosis. Arch Gun Psychiatry 4: i 54-159. Gammon GD, Hafez H, Docherty JP (1980): Chlorpromazine and immunologic considerations of schizophrenia. Ann Intern Mud 92:441.-.442. Ganguli R, Rabin BS (1989): Differences in inter-
738
BIOLPSYCHIATRY 1992;32:735-738
leukin-2 production in blacks and whites. N Engl J Med 320--399. Ganguli R, Brar JS (1992): Generalizability of first episode studies in schizophrenia. Schizophr Bull 18(3):436-469. Ganguli R, Rabin BS, Kelly RH, Lyre M, Raghu U (1987): Clinical and laboratory evidence of autoimmunity in acute schizophrenia. Ann NY Acad Sci 496;676-685. Ganguli R, Rabin BS, Kelly RH (1989): Multiple autoantibodiesand autoimmunedisease in schizophrenic patients: Evidence for an autoimmune pathogenesis. In Hadden JW, Masek K, Nistico (3 (eds), hlteractions Among CNS, Neuroendo. crine and bnmune Systems. Rome-Milan: Pythagora Press, 365-384. Krawcicka M, Goldberg D, Waughn N (1977): A standard psychiatric scale for rating psychotic patients. Acta Psychiatr Scand 55:299-308. Kroemer G, Andreu JL, Gonzalo JA, Gutierrez-Ra. mos JC, Martinez-AC (1991): Interleukin-2, autotolerance, and autoimmunity. Adv Immunol 50:147-235. Montgomery SA, Asberg M (1979): A new depression scale designed to be se~.~+.tiveto change. Br J Psychiatry 134:382-389. Overall JE, Gorham DR ( 1962):The Brief Psychiatric Rating Scale. Psychol Rep 10:799-812. Quismorio FP, Bjamason DF, Kiely WF, Dubois EL,
Brief Reports
Friou GJ (1975): Antinuclear antibodies in chronic psychotic patients ~reated with chlorpromazine. Am J Psychiatry 132(!!): 1204-1206. Roitt IM, Brostoff J, Male DK (eds) (1989): Immunology. New York: CV Mosby. Rose NR (1991): Characteristics of autoimmune disease. J Invest Dermatol 96:87S. Sirota P, Schild K, Firer M, et al (1991): Autoantibodies to DNA in multicase families with schizophrenia. Biol Psychiatry 29(9A): I03A. Spitzer RL, Endicott J, Robins E (1978a): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 35:773-782, Spitzer RL, Endictt J, Robins E (1978b): The Schedule for Affective Disorders and Schizophrenia (SADS). New York: New York State Psychiatric Institute. Stead WW, Senner JW, Reddick WT, Lofgrcn .IP (1990): Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engi J Med 322:422-42?. Yannitsi SO, Manoussakis MN, Mavridis AK, et al (1990): Factors related to the presence of autoantibodies in patients with chronic mental disorders. Biol Psychiatry 27:747-'/55. Zarrabi MH, Zucker S, Miller F (1979): Immunologic and coagulationdisorders in chlorpromazine-treatcd patients. Ann Intern Med 91:194-199.