Cell- and Single Molecule-Based Methods to Detect Anti- N -Methyl-D-Aspartate Receptor Autoantibodies in Patients With First-Episode Psychosis From the OPTiMiSE Project

Abstract

Circulating autoantibodies against glutamatergic N-methyl-D-aspartate receptor (NMDAR) have been reported in a proportion of patients with psychotic disorders, raising hopes for more appropriate treatment for these antibody-positive patients. However, the prevalence of circulating autoantibodies against glutamatergic NMDAR in psychotic disorders remains controversial, with detection prevalence rates and immunoglobulin classes varying considerably between studies, perhaps because of different detection methods. Here, we compared the results of serum assays for a large cohort of patients with first-episode psychosis using classical cell-based assays in three labs and a single molecule-based imaging method. Most assays and single molecule imaging in live hippocampal neurons revealed the presence of circulating autoantibodies against glutamatergic NMDAR in approximately 5% of patients with first-episode psychosis. However, some heterogeneity between cell-based assays was clearly observed, highlighting the urgent need for new sensitive methods to detect the presence of low-titer autoantibodies against glutamatergic NMDAR in seropositive patients who cannot be clinically identified from seronegative ones.

Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders

“…Possible contributory factors include the lack of a control group in many studies, variability in terms of diagnosis and illness chronicity (frequently not reported in detail), and differences among studies with respect to how antibodies were tested, making interpretation of the results difficult, particularly given that there is ongoing debate about the most sensitive and specific methods for antibody detection. Regarding the latter point, the most frequently used method in the reviewed studies (the commercially available fixed CBA) is believed to have high specificity but lower sensitivity [14, 41]. Considering this, it is curious that those studies that found seropositivity in both patients and controls tended to use the commercial CBA, whereas those that only found seropositivity in patients used live CBAs.…”

“…Nonetheless, given the available information, diagnostic differences between samples do not appear to be responsible. For instance, although the vast majority of negative studies included patients with DSM IV, DSM IV-TR, DSM 5, or ICD-10 schizophrenia diagnoses, among numerous other diagnoses, so too did most of the positive studies [10-12, 14, 16], and two of these studies explicitly reported finding antibody positivity in patients with a diagnosis of schizophrenia [10, 14]. Additionally, although the other two positive studies did not report antibody positivity results according to diagnosis, they only included patients with schizophrenia and schizoaffective disorder [11, 12].…”

“…Additionally, although the other two positive studies did not report antibody positivity results according to diagnosis, they only included patients with schizophrenia and schizoaffective disorder [11, 12]. Other diagnoses explicitly reported to be associated with antibody positivity include cannabis-induced psychosis, “acute and transient psychotic disorder” and bipolar affective disorder [16], schizophreniform disorder [14, 16], and first-episode psychosis, defined as having a score of at least 4 on one of numerous positive symptom Positive and Negative Syndrome Scale (PANSS) items [15]. Finally, no clear diagnostic pattern emerges when comparing those studies that found seropositivity in patients but not in healthy controls to those that found seropositivity in both groups.…”

“…Of the seven positive studies, four used a commercially available fixed cell-based assay (CBA) [10-12, 16], two used a live CBA [13, 15], and one used both, as well as a single molecule-based imaging method, for the sake of comparing approaches [14]. The majority of negative studies also used the same aforementioned commercially available CBA (or a modification of it) [17-22, 24-29], and four of these studies also included immunohistochemistry for further testing [19, 26-28].…”

“…It has been suggested that relying on any single method of detecting antibodies in serum may increase the risk of false-positive and false-negative results [27]. Notably, while three studies that included multiple antibody detection methods were entirely negative [19, 26, 27], one study that included both live and fixed CBAs found seropositivity using both assays, but the authors do highlight that the choice of CBA influenced the results [14]. While the selection and interpretation of antibody detection methods may be an ongoing point of debate, the inclusion of a control group can help make sense of findings and assist in safeguarding against the misinterpretation of false-positive results.…”