Ganglioside antibodies in schizophrenia and major depression

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BIOL PSYCHIATRY 1992;32:728 730

BRIEF REPORTS

Ganglioside Antibodies in Schizophrenia and Major Depression Andreas Stevens and Michael Weller*

Introduction Ganglioside antibodies have beet~ reported to occur in a number of neurological diseases. Altered immune function and abnormal antibodies have also been implied in schizophrenia and major depression (DeLisi and Crow 1986; King and Cooper 1989; Stein et al 1991; Shima et al 1991). However, in schizophrenic patients, Pelonero et a| (1990) have found no significant antibody titers against GM 1 and brain cerebrosides, and, to the best of our own knowledge, there is no such study in depressive patients.

Patients We studied 47 inpatients with acute schizophrenia (25 men aged 31.1 - 5.7 years, 22 women aged 31.1 • 9.8 years). Subtypes ineluded the paranoid (n -- 22), the disorganized (n = 12), and the undifferentiated (n - 13) type. Curt'ant medication were phenothiazines (n "- 15), butyrophenones (n = 14), elozapin (n -- 13), tricyclic antidepressants (n -- 2), and benzodiazepines (n - 15). Five patients were drug free. Mean duration of illness was 6.2 ± 7.1 years, average daily neuroleptic dose was

From the Department of Psychiatry, University of TObinsen, Germany, *Current address: National Institute of Mental Health, Clinical Neutoscience Branch, Section of Molecular Pharmacology, Bethesda, MD, USA, Address reprint requests to Andreas Stevens, M.D., Department of Psychiatry, University of Ttibingen, Osianderstr 22, D.7400 T0bingen, Germany. Received January 3, 1992; revised july 20, 1992.

© 1992 Society of Biological Psychiatry

830 - 315 chlorpromazine (CPZ) equivalents, average cumulative dose was 384* 10~ "4-412" 103 CPZ equivalents. Twenty-one patients had a major depressive episode (9 men, aged 40.7 __. 7.6 years, 12 women, aged 41.2 ~: 11.3 years); mean duration of illness was 8.4 - 5.3 years; 11 had recurrent illness; bipolar disorder was excluded. Medication was tricyclic antidepressants (n ~14) and benzodiazepines (n = 3). Diagnosis was established by DSM-III-R criteria (American Psychiatric Association 1987). Written consent was obtained. Excluded were patients and controls with autoimmune disease, neoplasms, recent brain injury or surgery; abnormal red blood cell sedimentation rate, urinalysis, serum protein electrophoresis, and liver enzymes. A general physical examination was performed on "healthy subjects" and medical patients; absence of psychiatric disease was verified by questioning. Nonpsychiatric controls thus included 7 healthy volunteers (mean age 29,2 4- 3.5 years), 24 medical patients with diagnoses of gastrointestinal and cardiopulmonary conditions (mean age 41.8 __ 11 years), and 20 neurological patients with noninflammatory conditions (38.7 __ 12,5 years). Peripheral blood was obtained through venipuncture, centrifuged, and stored at -20"C.

Materials and Methods Total serum lgM and IgG were determined by nephelometry and enzyme-linked immunosorbent assay (ELISA) (Weller et al 1991). Serum 0006-3223/92/$05.00

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Table 1. Serum lgG and IgM Antibody Titers (Mean _+ SD) to Gangliosides in Patients with Schizophrenia (n = 47) and Major Depression (n = 21) Schizophrenia GMI CM2 GM3 AGM! GDla Gdlb GTIb

Majordepressio~

IgG

lgM

1.04.4. 0.22 1.13 .4- 0.26" 1.08 .4- 0.24 i.13 ± 0.28" 1.15 4- 0.24" !.07 - 0.20 1.09 -*- 0.19"

0.96.4- 0.37 1.00 4- 0.38 1.00 "*" 0.;;9 1.09 -+ 0.33 0.95 4- 0.36 0.99 ± 0.36 0.95 4- 0.38

IgG 1.04 _ 1.11 41.07 ± 1.11 1.05 41.05 41.07.4-

Controls

IgM

0.18 0.14" 0.15 0.15 0.14 0.13 0.15

0.95 0.95 1.01 1.13 0.91 0.95 0.91

4--. ± 444±

0.32 0.29 0.32 0.35 0.29 0.32 0.31

IgG 1.00 1.00 1.00 !.00 1.00 1.00 1.00

4- 0.15 "*" 0.16 4- 0.19 _ 0.20 4- 0.15 4- 0.13 ± 0.13

lgM 1.00 ± !.00.41.00 41.00 ± 1.00 4i.00 41.00 4-

0.28 0.28 0.25 0.21 0.27 0.26 0.26

'Significant (p < 0.03) elevation comparedwith the combined control groups. To control for interassay variation, the patient values are given as rntio to the internal standards defined as '*1.00,"

lgG and lgM antibodies to gangliosides GMI, GM2, GM3, AGMI, Gdla, Gdlb, GTIb (Sigma, St. Louis, USA) were estimated according to Marcus et al (1989). Micro-ELISA plates (MI29A, Dynatech, Denkendorf, Germany) coated with ganglioside antigee- (150 ng/well) for 24 hr at 4°C were rinsed and incubated for 24 hr at 4°C with patient sera (assayed in triplicate). Captured serum IgG and lgM antibodies were labeled by anti-human IgG (A-5403) and lgM (A-3914) alkaline phosphatase (AP) conjugates (Sigma). Conversion of 0.5 g/L pnitrophenyle phosphate (Merck, Darmstadt, Germany) was read as optical density (OD) at 405.4 nm in an ELISA-re,ader (Flow, Meckenhein, Germany). The sera from seven healthy volunteers served as internal standards. Their mean ODs were defined to assume the value "1.00," and measures of variance were transformed accordingly, the same transformation procedure was applied to patient samples. Statistical analysis included Student's t-test, analysis of variance (ANOVA), multiple linear correlation analysis, and canonical discriminant analysis. Significance was assumed atp < 0.03.

(51 nonpsychiatric "controls"). Neither schizophrenic nor depressive patients had abnormal serum IgG or IgM levels. The results for gangIioside antibody titers are summarized in Tables 1 and 2. Data were normally distributed and no effect of age or gender was found in either group. In schizophrenic patients, elevated mean antibody fiters were found for GM2, AGMI, GDIa, and GTIb; in the depressive patients, only for GM2. Titers elevated above a symmetrical interval of confidence (calculated for p < 0.03 from the controls) against at least one ganglioside were found in 21/47 of the schizophrenic and fin 6/21 of the depressive patients (Table 2). By ANOVA, no effects for age, gender, duration of illness, subtype of disease, and current medication was found. Discriminant analysis based upon IgG antibodies against GMI, GM2, GM3, AGM1, and GDIa classified only 40% of the cases correctly as schizophrenic, depressive, or control, which is not significantly different from the a priori probability.

Results

Discussion

ANOVA revealed no differences among tile three control groups. Combined, a KolmogorovSmirnov one-sample test did not reject the assumption of a normal distribution. They were hence used as one normally distributed sample

The detection of lgG antibodies reactive with gangliosides in sera of patients with schizophrenia and major depression does not provide evidence for aberrant immune 7unction in major psychoses. Because the definition of control

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Table 2. Relative Incidence of Antibody Titers Elevated Above the 3rd Percentile in 47 Schizophrenic and 21 Depressive P~tients Schizophrenia Major depression

GMI GM2 GM3 AGM1 GDIa Gdlb GTIb

lgG (%)

IgM (%)

IgG (%)

IgM (%)

17 10 13 15 17 2 6

8 8 8 13 8 I0 15

4 0 4 0 2 0 2

4 2 2 6 2 2 8

groups will be crucial to the normal ranges obtained and no well.documented normal values are available, the study presented here takes great care to eliminate bias introduced by including three groups of nonpsychiatric controls. In contrast to previous findings (Legros et al 1985), total levels of serum lgG and IgM were not altered in schizophrenic and depressive patients as compared with controls. In schizophrenia and major depression, elevated mean IgG titers and normal mean lgM titers would suggest a chronic antigen exposure rather than a recent immunologic event. Apart from pathological titers occurring more frequently in psychiatric patients than in controls, there was no evident pattern of antibodies allowing reclassification of patient sera by discriminant analysis. This indicates that elevated ganglioside antibody titers are not specific for diagnoses. The observation that about one-half of the schizophrenic patients and a quarter of the depressive patients show elevated antibody titers against one or more gangliodsides whereas the rest does not, may just point out the heterogeneity of biological measures in major psychoses. No significant effects of age, gender, diagnostic subtype, current medication, and duration of illness could be demonstrated. However, possible effects of current medication on the ELISA were not evaluated. In summary, the findings presented here are essentially negative. Elevated antibody titers against gangliosides do occur more frequently in psychiatric patients than in medical and neu-

rological controls, but there is no characteristic antibody pattern.

References American Psychiatric Association (1987): Diagnostic and statistical manual of mental disorders (ed 3), revised. American Psychiatric Association, Washington, DC, DeLisi LE, Crow TJ (1986): Is schizophrenia a viral or immunologic disorder? Psychiatr Ciin North Am 9:115-132. Legros S, Mendlewicz J, Wybran J (1985): lmmunoglobulins, autoantibodies and other serum protein fractions in psychiatric disorders. Fur Arch Psychiatr Neurol Sci 235:9-1 i. King DJ, Cooper SJ (1989): Viruses, immunity and mental disorder. Br J Psychiatry 154:1-7. Marcus DM, Latov N, Hsi BP, Gillard ilK, and participating laboratories (1989): Measurement and significance of antibodies against GMI ganglioside. Report of a Workshop, 18 April 1989, Chicago, III, USA. J Neuroiramunol 25:255259. Pelonero AL, Panduragi AK, Calabrese VP 0990): Autoantibodies to brain lipids in schizophrenia. Am J Psychiatry 147:661-662. Shima S, Yano K, Sugiura M, Tokunaga Y (1991): Anticerebral antibodies in functional psychoses. Biol Psychiatry 29:322-328. Stein M, Millner AH, Trestman RL (1991): Depression, the immune system and health and illness. Arch Gen Psychiatry 48:171-177. Waller M, Stevens A, Summer N, Wieth61ter H, Dichgans J (1991): Cerebrospinal fluid interleukins, immunoglobulins, and fibronectin in neuroborreliosis. Arch Neurol 48:837-841.