Psychiatric Autoimmunity: N-Methyl-D-Aspartate Receptor IgG and Beyond.

BACKGROUND: Descriptions of psychiatric autoimmunity beyond N-methyl-D-aspartate (NMDA) receptor encephalitis are sparse. OBJECTIVE: To report the autoimmune psychiatric spectrum currently recognized in Mayo Clinic practice. METHODS: Medical record review, testing of stored serum and cerebrospinal fluid for IgGs reactive with synaptic receptors and ion channels, neuronal nuclear and cytoplasmic antigens (including glutamic acid decarboxylase 65-kDa isoform) and case-control comparison were conducted. Patients were categorized into group 1, all adult psychiatric inpatients tested for neural autoantibodies (2002-2011; n = 213), and group 2, all Mayo NMDA receptor IgG-positive patients (2009-2013; n = 13); healthy control subjects were also included (n = 173). RESULTS: In group 1, at least 1 serum autoantibody (but not NMDA receptor IgG) was detected in 36 of 213 psychiatric inpatients. In total, 12 patients were determined retrospectively to have high-likelihood autoimmune encephalitic diagnoses. The most commonly detected autoantibody specificities were voltage-gated potassium channel ([Kv1] VGKC) complex (6) and calcium channel (P/Q type or N type; 5). Symptoms seen were as follows: depressive (8), anxious (7), psychotic (7), disorganized (5), suicidal (3), manic (1) and catatonic (1). In group 2, among 13 NMDA receptor IgG-positive patients, 12 had encephalitis; their psychiatric symptoms were as follows: depressive (9), catatonic (9), disorganized (8), anxious (8), psychotic (7), manic (6), and suicidal (3). Catatonic symptoms were more common in the 12 NMDA receptor IgG-positive patients than in the 12 group 1 patients with high likelihood of encephalitis (p = 0.002). Antibody positivities were usually low positive in value among healthy controls (12 of 16 vs 3 of 12 group 1 encephalitis cases, p = 0.025). NMDA receptor IgG was not detected in any healthy control subject. CONCLUSIONS: A spectrum of psychiatric autoimmunity beyond NMDA-R IgG may be under-recognized. Diagnosis is facilitated by combining results of comprehensive psychiatric, laboratory, radiologic, and electrophysiologic evaluations.

HLA antigens and schizophrenia.

We typed 45 schizophrenic patients for 35 HLA antigens and compared their frequencies with 1,263 population controls. No significant differences between schizophrenics and controls were found. When the schizophrenics were subtyped, a significant (P less than .05) excess of Aw26 was found among the hebephrenics, compared with the population controls. When the published literature on schizophrenia-HLA associations was surveyed, none of the reported associations were found to be consistent across studies. Some possible explanations for the heterogeneity among studies are discussed and it is concluded that an association between schizophrenia and any of the HLA antigens has not yet been demonstrated.

HLA antigens and subtypes of schizophrenia.

Studies on HLA antigens in schizophrenia have produced conflicting results, but there has been greater agreement when clinical subtypes of the disorder have been separated. In view of this, we reassessed 68 previously studied patients with hospital diagnoses of schizophrenia and, while blind to their HLA types, used operational criteria to define clinical subtypes. We compared and combined the results with those from all available similar studies. Those of our patients who fulfilled operational criteria for paranoid schizophrenia showed a nonsignificant increase in HLA A9 as compared with controls. The magnitude of the increase was similar to that from all previous reports, and when data from all sources were combined, the evidence for an association between HLA A9 and paranoid schizophrenia was consistent and highly significant. Patients who were diagnosed as suffering from hebephrenic schizophrenia showed significant increases in HLA A1 and B8 compared with controls. An association between hebephrenia and A1, but not B8, remained on combining the results with those of other studies.

Anti-histone antibodies in schizophrenia and affective disorders.

Sera from 81 psychiatric patients (51 with schizophrenia and 30 with affective disorders) were analyzed using several assays in parallel for the presence of non-organ-specific autoantibodies, namely anti-nuclear antibodies, anti-deoxyribonucleic acid antibodies (native and denatured DNA), anti-histone antibodies, anti-centromere antibodies, and anti-nuclear antigen antibodies. Nine out of the 81 sera studied were positive for the presence of anti-nuclear antibodies. Moreover, in 15 patients, significant titers of anti-histone antibodies were detected. No correlation can be drawn concerning the presence of anti-histone antibodies and the clinical situation. Although no clear association was noted with a specific class of drugs, it cannot be excluded at present that the therapeutic regimen received by the patients may explain the results observed.

[Schizophrenia and histocompatibility antigens]. / Schizophrénies et antigènes d'histocompatibilité.

Schizophrenias have a genetical support as it is now proved by the study of twins born from schizophrenic parents and of the adopted children of schizophrenics. The HLA typing brings an additional argument in favour of this hypothesis. After a recall of data concerning the system of tissular histocompatibility, the results are given of the HLA typing of a population of 65 schizophrenics (59 men, 6 women) including 27 hebephrenics and 38 paranoïds. The paranoïd group is clearly individualized from a genetic point of view. If 40% of the schizophrenics carry the A9 antigen versus 21,2% found in the normal population, 47,4 % of the paranoïd schizophrenics present this antigen (X2) = 12,16 p less than 0,001). The association of the two antigens A9 and CW4 is even more significant: 14,3 % of the total schizophrenic population, as opposed to 2,7 % in the normal population (X2) = 13,3 p less than 0,0005). The paranoid group reached a rate of 24,3% (x(2) = 27,3 p less than 0,0005). A subject carrier of both antigens A9 + CW4 has 11,5 times more the risk of being a paranoïd schizophrenic than a subject not possessing these two antigens.

T-lymphocyte subpopulations in schizophrenic patients.

T-lymphocyte subpopulations were examined in the peripheral blood of 30 acute schizophrenic patients and compared with 30 age- and sex-matched patients with non-inflammatory neurological diseases. Significant increases in the numbers of Pan-T and T-helper cells were found in schizophrenic patients compared to the controls. The interindividual variability of values in the group of schizophrenic patients was greater than in the group of neurological patients.

The HLA system and the clinical response to treatment with chlorpromazine.

A group of 33 schizophrenic patients were typed for HLA-SD antigens and their qualitative clinical responses to chlorpromazine therapy determined. A highly significant positive correlation was found between response to chlorpromazine and HLA-AI positive, while HLA-A2 positive subjects showed a significant negative correlation to chlorpromazine treatment. In a second group of 17 patients the clinical response to chlorpromazine were evaluated quantitatively, by WPRS, in HLA-AI positive and HLA-AI negative patients. There were no pre-treatment differences in the scores. After treatment the scores of positive patients were significantly lower, indicating that they responded to a greater degree. Since the frequency of HLA-AI in hebephrenic patients is higher than that in other schizophrenics this may explain our earlier finding that hebephrenics, as a group, respond better to chlorpromazine than do other schizophrenics.