Psychotic disorders are debilitating mental illnesses associated with abnormalities in various neurotransmitter systems. The development of disease-modifing therapies has been hampered by the mostly unknown etiologies and pathophysiologies. Autoantibodies against several neuronal antigens are responsible for autoimmune encephalitis. These autoantibodies disrupt neurotransmission within the brain, resulting in a wide range of psychiatric and neurologic manifestations, including psychosis. The overlap of symptoms of autoimmune encephalitis with psychotic disorders raised the question as to whether autoantibodies against a number of receptors, ion channel and associated proteins could ultimately be responsible for some forms of psychosis. Here we review our current knowledge, on antibody mediated autoimmunity in psychotic disorders, the different diagnostic methods and their limitations, as well as on varying therapeutic approaches targeting the immune system.

Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.

Little is known about the etiology of neuropsychiatric disorders. The identification of autoantibodies targeting the N-methyl-d-aspartate receptor (NMDA-R), which causes neurological and psychiatric symptoms, has reinvigorated the hypothesis that other patient subgroups may also suffer from an underlying autoimmune condition. In recent years, a wide range of neuropsychiatric diseases and autoantibodies targeting ion-channels or neuronal receptors including NMDA-R, voltage gated potassium channel complex (VGKC complex), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), γ-aminobutyric acid receptor (GABA-R) and dopamine receptor (DR) were studied and conflicting reports have been published regarding the seroprevalence of these autoantibodies. A clear causative role of autoantibodies on psychiatric symptoms has as yet only been shown for the NMDA-R. Several other autoantibodies have been related to the presence of certain symptoms and antibody effector mechanisms have been proposed. However, extensive clinical studies with large multicenter efforts to standardize diagnostic procedures for autoimmune etiology and animal studies are needed to confirm the pathogenicity of these autoantibodies. In this review, we discuss the current knowledge of neuronal autoantibodies in the major neuropsychiatric disorders: psychotic, major depression, autism spectrum, obsessive-compulsive and attention-deficit/hyperactivity disorders.

Objective To describe the unique case history of a patient with mGluR1 antibodies, with mainly limbic and without cerebellar symptoms. Methods A 50-year-old woman initially presented with focal seizures with epigastric rising and déjà-vu sensations, next to cognitive complaints, and musical auditory hallucinations. MRI, EEG, and neuronal autoantibody tests were performed. Results EEG findings showed slow and sharp activity (sharp waves and sharp-wave–slow-wave complex) in the left temporal lobe. A test for autoantibodies was negative initially. Because of persistent symptoms, serum and CSF were tested 4 years later and found positive for mGluR1 antibodies. Treatment started with monthly IV immunoglobulins and azathioprine that was replaced by mycophenolate mofetil later. Especially cognitive symptoms and hallucinations did not respond well to the treatment. During treatment, mGluR1 antibodies remained present in CSF. Discussion Whereas cerebellar symptoms are present in 97% of mGluR1-positive cases, our patient presented without ataxia. Therefore, we suggest that the clinical presentation of patients with mGluR1 antibodies is probably more diverse than previously described. Testing for mGluR1 antibodies should be considered in patients with limbic encephalitis and epilepsy, especially when negative for more common antibodies.

A nine-year-old boy manifested with headache, progressive mild cognitive decline and hemiparesis, but without clinical epileptic seizures (with abnormal EEG waves). Brain magnetic resonance imaging (MRI) showed bilateral cortical lesions mainly on the right hemisphere, and new lesions developed in frontal, parietal, occipital and temporal lobes around the old lesions presenting as a lace-like or ring-like enhancement in T1 with contrast over a disease course of five years. A suspected diagnosis of primary angiitis of the central nervous system was initially considered. Treated with high-dose corticosteroids, intravenous immunoglobulins and monthly pulse cyclophosphamide, his symptoms worsened with the intracranial lesion progression. Brain biopsy of the right frontal lobe was performed nearly five years after onset; prominent neuronal loss, a microglial nodule, as well as parenchymal and perivascular lymphocytic infiltrate within the cortex were found, which coincided with RE pathology changes. Encouragingly, after a regimen of rituximab, lesions on the follow-up brain MRI tended to be stable. Apparently, it was immune-mediated, but did not strictly fit any known disease entity, although it was similar to RE. We summarize this unique case, including clinical characteristics, imaging and pathology findings. We also discuss the diagnosis and treatment, focusing on comparison to RE as well as other possible neurological diseases.

The conflict of interest section was missing in the published paper [1]. It has been updated as follows: