[Autoinmune psychosis]. / Psicosis autoinmune.

With the advent of the description of autoimmune encephalitis by different neuronal cell-surface antibodies (anti-NMDAr, among others) and that psychosis may be the only manifestation without neurological symptoms (epilepsy, movement disorders, autonomic dysfunction, altered state of consciousness) in 6.5 % of patients, the term "autoimmune psychosis" has become remarkably interesting among researchers. In 2020, an international consensus for the description and diagnostic approach of autoimmune psychosis was created. Through this consensus, by taking different criteria into account, the definition of autoimmune psychosis was proposed at different degrees of certainty (possible, probable, and defined). The purpose of these criteria is to underpin the autoimmune origin in patients who present psychosis with atypical characteristics, thus justifying the realization of laboratory studies and complementary clinical tests (lumbar puncture, electroencephalogram, and magnetic resonance imaging of the brain); in addition, these criteria are applied in patients with psychosis without neurological symptoms that do not fully meet the criteria of autoimmune encephalitis. As in autoimmune encephalitis, the early initiation of immunotherapy has a direct impact on the functional prognosis of patients, so an early initiation of treatment must be considered in clinical scenarios of probable or definite autoimmune psychosis.

Con el advenimiento de la descripción de las encefalitis autoinmunes por diferentes anticuerpos neuronales de superficie (anti-NMDAr, entre otros) y que la psicosis puede ser la única manifestación sin síntomas neurológicos (epilepsia, alteraciones del movimiento, disautonomías, alteración del despierto) en 6.5 % de los pacientes, el término psicosis autoinmune ha retomado gran interés entre los investigadores. En 2020 se creó un consenso internacional para la descripción del término "psicosis autoinmune" y su abordaje diagnóstico. A través de este consenso, considerando diferentes criterios, se propone la definición de psicosis autoinmune en diferentes grados de certeza (posible, probable y definida). La finalidad de estos criterios es sustentar el origen autoinmune en pacientes que presenta psicosis con características atípicas, justificando así la realización de estudios de laboratorio y gabinete complementarios (punción lumbar, electroencefalograma, imagen de resonancia magnética de encéfalo); además, estos criterios se aplican a pacientes con psicosis sin síntomas neurológicos que no cumplen completamente con los criterios de encefalitis autoinmune. El inicio temprano de la inmunoterapia impacta directamente en el pronóstico funcional de los pacientes; se debe considerar el inicio temprano de tratamiento en cuadros clínicos de psicosis autoinmune probable o definida.

First Episode Psychosis and Schizophrenia Are Systemic Neuro-Immune Disorders Triggered by a Biotic Stimulus in Individuals with Reduced Immune Regulation and Neuroprotection.

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory systems (CIRS) and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AN-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of FES. However, the protein-protein interaction (PPI) network of FEP/FES is not established. The aim of the current study was to delineate a) the characteristics of the PPI network of AN-FEP and its transition to FES; and b) the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. Toward this end, we used PPI network, enrichment, and annotation analyses. FEP and FEP/FES are strongly associated with a response to a bacterium, alterations in Toll-Like Receptor-4 and nuclear factor-κB signaling, and the Janus kinases/signal transducer and activator of the transcription proteins pathway. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation, and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation, in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin and Wnt/catenin signaling, and adherens junction organization. Multiple interactions between reduced brain derived neurotrophic factor, E-cadherin, and ß-catenin and disrupted schizophrenia-1 (DISC1) expression increase the vulnerability to the neurotoxic effects of immune molecules, including cytokines and complement factors. In summary: FEP and FES are systemic neuro-immune disorders that are probably triggered by a bacterial stimulus which induces neuro-immune toxicity cascades that are overexpressed in people with reduced anti-inflammatory and miRNA protections, cell-cell junction organization, and neurotrophin and Wnt/catenin signaling.

Immunological investigations of the cerebrospinal fluid in patients with recent onset psychotic disorders: A study protocol.

BACKGROUND: Though many previous studies have indicated immunological alterations in psychotic disorders, the role and prevalence of neuroinflammation is still unknown. Studies previously investigating immune related biomarkers in the cerebrospinal fluid (CSF) of these patients are mainly small studies on few markers, and many have not compared patients to healthy controls. METHODS: We will conduct a large case-control study including at least 100 patients with recent onset psychotic disorders and 100 sex- and age matched healthy controls. The cases will include patients diagnosed with a psychotic disorder according to ICD-10 (F20/F22-29) within a year prior to inclusion. We will collect both CSF, blood and fecal samples, to gain insight into possible immunological alterations. The psychopathology of all participants will thoroughly be evaluated using the SCAN interview, and multiple rating scales covering different symptom groups. All participants will partake in a detailed neurological examination, including the Neurological Evaluation Scale assessing neurological soft signs. Additionally, we will assess cognitive functioning, evaluate quality of life and level of functioning, and collect data on a broad array of possible confounders. Our primary outcomes will include CSF leucocytes, CSF/serum albumin ratio, CSF total protein, IgG index, CSF levels of IL-6 and IL-8, and presence of antineuronal autoantibodies in CSF and blood. For our secondary outcomes, exploratory analyses will be performed on a broader panel of neuroimmunological markers. All participants will be invited for a follow-up visit to assess longitudinal changes. The current study is part of a larger CSF biobank build-up for severe mental disorders (PSYCH-FLAME). DISCUSSION: This study will represent the largest investigation of CSF in patients with psychotic disorders compared to healthy controls to date. We expect the study to contribute with new, important knowledge on pathophysiological mechanisms, and to help pave the way for future investigations of individualized treatment options. TRIAL REGISTRATION: The study is approved by The Regional Committee on Health Research Ethics (Capital Region, j.no: H-16030985) and The Danish Data Protection Agency (j.no: RHP-2016-020, I-Suite no.: 04945).

An observational study on the association of anti-thyroid autoantibodies with clinical, EEG, MRI, FDG-PET, cerebrospinal fluid and anti-neuronal antibody findings in 530 patients with schizophreniform and affective disorders.

INTRODUCTION: Although the link between autoimmune thyroiditis and mental illnesses is well established, the precise underlying pathophysiology and the influence of anti-thyroid antibodies on diagnostic findings require further research. PATIENTS AND METHODS: A total of 530 patients with schizophreniform and affective syndromes were screened for anti-thyroid antibodies against thyroid peroxidase (TPO), thyroglobulin (TG), and thyroid-stimulating hormone receptor (TSH-R). The patient group analyzed here is a patient subgroup of a previously published cohort (Endres et al., 2020, Translational Psychiatry). The anti-thyroid antibody positive (N = 91) and negative (N = 439) patients were compared in terms of various clinical parameters, routine cerebrospinal fluid (CSF) findings, and the number of positive anti-neuronal antibodies in serum and/or CSF, as well as electroencephalography (EEG), magnetic resonance imaging (MRI), and [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) findings. RESULTS: Anti-TPO antibodies were increased in 17%, anti-TG antibodies in 15%, and anti-TSH-R antibodies in 2% of all patients. In CSF, higher protein concentrations (p = 0.018) and albumin quotients (p = 0.008) were found in the anti-thyroid antibody positive patient group. Also, there were more patients with elevated age-corrected albumin quotients in this group (p = 0.031). FDG-PET hypometabolism was significantly more frequent and the number of positive anti-neuronal intracellular antibodies was significantly higher in patients with anti-thyroid antibodies (p = 0.048, N = 29 and p = 0.032, N = 497 respectively). In addition, there was a trend for higher white blood cell (WBC) counts in all patients with anti-thyroid antibodies (p = 0.090). In the patient subgroup with anti-TPO antibodies this difference was statistically significant (p = 0.027). No relevant differences were found in the other CSF routine parameters, the number of anti-neuronal antibodies against cell surface antigens in serum and/or CSF, EEG and MRI findings. DISCUSSION: The present study provides evidence of impaired blood CSF barrier (BCSFB) function in patients with anti-TPO and anti-TG antibodies. An influence of anti-TG antibodies on BCSFB structures has been shown in previous laboratory studies, which reported that the antibodies bind to vascular smooth muscle cells. Due to BCSFB breakdown anti-thyroid antibodies might lead to increased autoimmune susceptibility. The alterations in the FDG-PET, WBC count, and anti-neuronal antibody findings against intracellular structures indicate that it could be useful to extend diagnostic investigations in patients with anti-thyroid antibodies. Further studies should investigate whether anti-thyroid antibodies can also act as "drivers of disease".

Clinical, Neuroimmunologic, and CSF Investigations in First Episode Psychosis.

OBJECTIVES: To report the neuropsychiatric features and frequency of NMDA receptor (NMDAR) and other neuronal immunoglobulin G antibodies in patients with first episode psychosis (FEP) and to assess the performance of reported warning signs and criteria for autoimmune psychosis (AP). METHODS: This was a prospective observational study of patients with FEP assessed for neuropsychiatric symptoms, serum and CSF neuronal antibodies (brain immunohistochemistry, cell-based assays, live neurons), and warning signs and criteria of AP. Previous autoimmune FEP series were reviewed. RESULTS: One hundred five patients were included; their median age was 30 (range 14-75) years, and 44 (42%) were female. None had neuronal antibodies. Two of 105 (2%) had CSF pleocytosis, 4 of 100 (4%) had brain MRI abnormalities, and 3 of 73 (4%) EEG alterations. Thirty-four (32%) and 39 (37%) patients fulfilled 2 sets of warning signs of AP, and 21 (20%) fulfilled criteria of possible or probable AP, yet none developed AP. The cause of FEP was psychiatric in 101 (96%) and nonpsychiatric in 4 (4%). During this study, 3 patients with psychosis caused by anti-NMDAR encephalitis were transferred to our center; 2 did not meet criteria for possible AP. Of 1,159 reported patients with FEP, only 7 (1%) had CSF studies; 36 (3%) had serum NMDAR antibodies (without definite diagnosis of AP), and 4 had CSF NMDAR antibodies (3 classic anti-NMDAR encephalitis and 1 with isolated psychiatric features). CONCLUSIONS: NMDAR antibodies were not found in patients with FEP unless they had anti-NMDAR encephalitis. Warning signs and criteria for AP have limited utility when neurologic symptoms are absent or paraclinical tests are normal. A diagnostic algorithm for autoimmune FEP is provided.

Prolactin, metabolic and immune parameters in naïve subjects with a first episode of psychosis.

BACKGROUND: Prolactin (Prl) is a pleiotropic hormone initially described for its regulation of lactation in mammals but later associated with metabolic and immune homeostasis, stress, inflammatory response and human behavior. Its regulation through dopamine receptors highlights its importance in psychiatry mostly because hyperprolactinemia is a common secondary side effect of dopamine antagonists. Despite its undeciphered patho-physiological mechanisms, hyperprolactinemia in naïve psychosis patients has been widely described. Its consequences might underlie the increased morbidity and early mortality found in naïve subjects as described in the general population where prolactin values have been correlated with inflammatory, immune and metabolic parameters. METHODS: We aimed to evaluate the correlation between prolactin values and other biochemical parameters (C-reactive Protein-CrP, blood cell count, lipid and hepatic profile, fasting glucose) in a cohort of first episode psychosis naïve subjects (N = 491) stratified by sex. Regression analyses with confounders were performed to evaluate the association. FINDINGS: Prl displayed significant correlations with C-Reactive Protein (CrP), Low-Density Lipoprotein (LDL), Aspartate Transaminase (AST) for females and High-Density Lipoprotein (HDL) and eosinophil count for males. However, and despite previous specific sex correlations, significant associations were described for CrP, HDL, LDL, AST and ALT without sex interaction and despite confounders such as age, Body Mass Index or smoking status. CONCLUSIONS: Our results show a specific relation of Prl with immune and metabolic parameters describing a heterogeneous pattern. Our results suggest that prolactin might underlie the excess of morbidity and early mortality in naïve patients through a specific pathway.

Classification of Psychoses Based on Immunological Features: A Machine Learning Study in a Large Cohort of First-Episode and Chronic Patients.

For several years, the role of immune system in the pathophysiology of psychosis has been well-recognized, showing differences from the onset to chronic phases. Our study aims to implement a biomarker-based classification model suitable for the clinical management of psychotic patients. A machine learning algorithm was used to classify a cohort of 362 subjects, including 160 first-episode psychosis patients (FEP), 70 patients affected by chronic psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder) with psychosis (CRO) and 132 health controls (HC), based on mRNA transcript levels of 56 immune genes. Models distinguished between FEP, CRO, and HC and between the subgroup of drug-free FEP and HC with a mean accuracy of 80.8% and 90.4%, respectively. Interestingly, by using the feature importance method, we identified some immune gene transcripts that contribute most to the classification accuracy, possibly giving new insights on the immunopathogenesis of psychosis. Therefore, our results suggest that our classification model has a high translational potential, which may pave the way for a personalized management of psychosis.

Influence of methodological and patient factors on serum NMDAR IgG antibody detection in psychotic disorders: a meta-analysis of cross-sectional and case-control studies.

BACKGROUND: Antibodies targeting the N-methyl-D-aspartate receptor (NMDAR) have been detected in patients with psychosis. However, studies measuring the IgG subclass in serum have provided variable estimates of prevalence, and it is unclear whether these antibodies are more common in patients than controls. Because these inconsistencies could be due to methodological approaches and patient characteristics, we aimed to investigate the effect of these factors on heterogeneity. METHODS: We searched Web of Science and Ovid (MEDLINE and PsycINFO) for cross-sectional and case-control studies published between Jan 1, 2000, and May 5, 2019, that reported NMDAR IgG antibody seropositivity in patients with psychosis. Pooled proportions and odds ratios (ORs) were derived using random-effects models. We estimated between-study variance (τ2) and the proportion of observed variance due to heterogeneity (I2). We then used univariable random-effects meta-regression analysis to investigate the effect of study factors on heterogeneity of proportions and ORs. Our protocol was registered on PROSPERO (CRD42018099874). FINDINGS: Of 1276 articles in the initial search, 28 studies were eligible for inclusion, including 14 cross-sectional studies and 14 case-control studies. In cross-sectional studies, NMDAR IgG antibodies were detected in 0·73% (95% CI 0·09-1·38; I2 56%; p=0·026) of patients with psychosis, and in case-control studies, patients with psychosis were not significantly more likely to be seropositive than healthy individuals (OR 1·57, 95% CI 0·78-3·16; I2 15%; p=0·20). Meta-regression analyses indicated that heterogeneity was significantly associated with assay type across both study designs, illness stage in cross-sectional studies, and study quality in case-control studies. Compared with studies using a fixed cell-based assay, cross-sectional and case-control studies using the live method yielded higher pooled prevalence estimates (0·36% [95% CI -0·23 to 0·95] vs 2·97% [0·70 to 5·25]) and higher ORs (0·65 [0·33 to 1·29] vs 4·43 [1·73 to 11·36]). In cross-sectional studies, the prevalence was higher in exclusively first-episode samples than in multi-episode or mixed samples (2·18% [0·25 to 4·12] vs 0·16% [-0·31 to 0·63]), and in case-control studies, higher ORs were reported in low-quality studies than in high-quality studies (3·80 [1·47 to 9·83] vs 0·72 [0·36 to 1·42]). INTERPRETATION: Higher estimates of NMDAR IgG antibody prevalence have been obtained with the live cell-based assay, and studies using this method find that seropositivity is more common in patients with psychosis than in controls. The effects of illness stage and study quality on heterogeneity were not consistent across study designs, and we provide clear recommendations for clinicians and researchers regarding interpreting these findings. FUNDING: None.

A commentary revisiting the viral hypothesis of schizophrenia: Onset of a schizophreniform disorder subsequent to SARS CoV-2 infection.

The viral hypothesis for schizophrenia has persisted for decades, initially supported by observed increases in psychoses subsequent to the influenza pandemic of the early twentieth century, and then later by evidence of elevated viral antibody titres particularly in schizophrenia patient populations. Several research studies have also focused on maternal infections during the second trimester of pregnancy and their long-term effects on fetal brain development, ultimately leading to schizophrenia. No specific virus has been implicated although a handful have received increasing attention. The current pandemic spreading the SARS CoV-2 corona virus world-wide is now showing anecdotal evidence of psychoses newly developing post viral exposure, implicating neuronal inflammation in crucial areas of the brain that could initiate psychotic symptoms. Time will tell if epidemiological data will, similar to the 1918 influenza pandemic, show that schizophrenia spectrum disorders increase after serious viral infections.

Oligodendrocyte myelin glycoprotein as a novel target for pathogenic autoimmunity in the CNS.

Autoimmune disorders of the central nervous system (CNS) comprise a broad spectrum of clinical entities. The stratification of patients based on the recognized autoantigen is of great importance for therapy optimization and for concepts of pathogenicity, but for most of these patients, the actual target of their autoimmune response is unknown. Here we investigated oligodendrocyte myelin glycoprotein (OMGP) as autoimmune target, because OMGP is expressed specifically in the CNS and there on oligodendrocytes and neurons. Using a stringent cell-based assay, we detected autoantibodies to OMGP in serum of 8/352 patients with multiple sclerosis, 1/28 children with acute disseminated encephalomyelitis and unexpectedly, also in one patient with psychosis, but in none of 114 healthy controls. Since OMGP is GPI-anchored, we validated its recognition also in GPI-anchored form. The autoantibodies to OMGP were largely IgG1 with a contribution of IgG4, indicating cognate T cell help. We found high levels of soluble OMGP in human spinal fluid, presumably due to shedding of the GPI-linked OMGP. Analyzing the pathogenic relevance of autoimmunity to OMGP in an animal model, we found that OMGP-specific T cells induce a novel type of experimental autoimmune encephalomyelitis dominated by meningitis above the cortical convexities. This unusual localization may be directed by intrathecal uptake and presentation of OMGP by meningeal phagocytes. Together, OMGP-directed autoimmunity provides a new element of heterogeneity, helping to improve the stratification of patients for diagnostic and therapeutic purposes.

Psychoses by Attacks from Subverted Mast Cells: A Role for Arterial Intramural Flow Badly Steered by the Nasal Ganglia?

Mechanisms of cortical psychoses are approached by complementing big data-driven genetics and imaging with a putatively subverted neurovascular "reverse plumbing" by arteries. The "cortical spread" of grey matter loss in schizophrenia and the mid-pericallosal "congestion" in fMRI of periodic catatonia - treatable electromagnetically along arteries - are interpreted in terms of the fastest interstitial outflow through the Cerebral IntraMural Reverse Arterial Flow-engine (CIMURAF, Treviranus 2018-19) draining "waste" via arterio-adventitial lymphatics to the neck. Such repetitively sliding segments of CIMURAF are wrung downstream by muscles likely steered by the neurovascular pterygopalatine ganglion. At the pericallosal artery, along its ideal long straight segment, this likely happens diverging from the mid-callosum towards the front and the back. In the case of a convergent inversion a mid-callosal clash will result, which is observable in psychoses as a mid-callosal high-flow-spot simultaneously with hyper-perfusions of branches and "backwatering" of pial vessels with reactive waste - till date interpreted psycho-mathematically. CIMURAF might also accelerate the perivascular intrusion of MCs by flushing autocrine signals (of which electro-magnetism moves the dipoles) through a putative periadventitial counter-current. Psychoses plausible occur through tryptase-mediated attacks operated by mast cells against oligodendrocytes' cytoskeleton (Medic 2009) and probably via complement-4 (Schizophrenia WG, 2014) against neurons. Usually MCs are essential long-lived "orchestrators" of homeostases and immune or barrier defences interacting with nerves, immunocytes, organs, and routes. MCs after somatic programming as to "destination & destiny" (Treviranus 2017a, 6.2., 2018) rapidly intrude also into the brain's parenchyma, first within the lymphatics and then putatively by crossing-over to extraluminal arterial routes. MCs transverse the BBBs, while macrophages only trespass in "disease" (Faraco et al. 2017). Both can be "subverted" by a list of microbes (and putatively blown up by COVID-19 within walls). Enuresis and MCs' reactions to clozapine add to the interactive support from (epi-)genetics and imaging.

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics.

Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.

A history of childhood trauma and allostatic load in patients with psychotic disorders with respect to stress coping strategies.

Elevated allostatic load (AL) index, which is a cumulative measure of biological dysregulations associated with stress exposure, has been demonstrated in patients with psychosis. However, it remains unknown whether a history of childhood trauma (CT) might contribute to elevated AL index in psychosis. Therefore, we aimed to investigate the association between AL index, a history of CT and coping styles in patients with psychotic disorders. Participants were 65 patients with schizophrenia-spectrum disorders and 56 healthy controls (HCs). The AL index was computed based on percentile distributions of 15 biomarkers in HCs. The AL index was significantly higher in patients with psychosis. A history of parental antipathy was associated with elevated AL index in both groups of participants. A history of any categories of CT and sexual abuse were associated with higher AL index only in patients with psychosis. Social diversion (seeking social interactions in case of stressful experiences) mediated the association between sexual abuse and the AL index in the group of patients. There was a significant direct effect of sexual abuse on the AL index (this specific CT was associated with higher AL index). However, indirect effect of sexual trauma on AL through social diversion was opposite to direct effect. Childhood adversities, especially sexual abuse and parental antipathy, might contribute to elevated AL index in patients with psychosis. The effect of sexual abuse on the AL index might be specific to psychosis. Engagement in social interactions in case of stressful situations might alleviate biological dysregulations associated with CT.

Autoimmune encephalitis as a differential diagnosis of schizophreniform psychosis: clinical symptomatology, pathophysiology, diagnostic approach, and therapeutic considerations.

Primary schizophreniform psychoses are thought to be caused by complex gene-environment interactions. Secondary forms are based on a clearly identifiable organic cause, in terms of either an etiological or a relevant pathogenetic factor. The secondary or "symptomatic" forms of psychosis have reentered the focus stimulated by the discovery of autoantibody (Ab)-associated autoimmune encephalitides (AEs), such as anti-NMDA-R encephalitis, which can at least initially mimic variants of primary psychosis. These newly described secondary, immune-mediated schizophreniform psychoses typically present with the acute onset of polymorphic psychotic symptoms. Over the course of the disease, other neurological phenomena, such as epileptic seizures, movement disorders, or reduced levels of consciousness, usually arise. Typical clinical signs for AEs are the acute onset of paranoid hallucinatory symptoms, atypical polymorphic presentation, psychotic episodes in the context of previous AE, and additional neurological and medical symptoms such as catatonia, seizure, dyskinesia, and autonomic instability. Predominant psychotic courses of AEs have also been described casuistically. The term autoimmune psychosis (AP) was recently suggested for these patients. Paraclinical alterations that can be observed in patients with AE/AP are inflammatory cerebrospinal fluid (CSF) pathologies, focal or generalized electroencephalographic slowing or epileptic activity, and/or suspicious "encephalitic" imaging findings. The antibody analyses in these patients include the testing of the most frequently found Abs against cell surface antigens (NMDA-R, CASPR2, LGI1, AMPA-R, GABAB-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], amphiphysin, GAD65), thyroid antigens (TG, TPO), and antinuclear Abs (ANA). Less frequent antineuronal Abs (e.g., against DPPX, GABAA-R, glycine-R, IgLON5) can be investigated in the second step when first step screening is negative and/or some specific clinical factors prevail. Beyond, tissue-based assays on brain slices of rodents may detect previously unknown antineuronal Abs in some cases. The detection of clinical and/or paraclinical pathologies (e.g., pleocytosis in CSF) in combination with antineuronal Abs and the exclusion of alternative causes may lead to the diagnosis of AE/AP and enable more causal therapeutic immunomodulatory opportunities.

The Neuroimmune and Neurotoxic Fingerprint of Major Neurocognitive Psychosis or Deficit Schizophrenia: a Supervised Machine Learning Study.

No studies have examined the immune fingerprint of major neurocognitive psychosis (MNP) or deficit schizophrenia using M1 macrophage cytokines in combination with chemokines such as CCL2 and CCL11. The present study delineated the neuroimmune fingerprint of MNP by analyzing plasma levels of IL-1ß, sIL-1RA, TNFα, sTNFR1, sTNFR2, CCL2, and CCL11 in 120 MNP versus 54 healthy controls in association with neurocognitive scores (as assessed with the Brief Assessment of Cognition in Schizophrenia) and PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. MNP was best predicted by a combination of CCL11, TNFα, IL-1ß, and sIL-1RA which yielded a bootstrapped (n = 2000) area under the receiver operating curve of 0.985. Composite scores reflecting M1 macrophage activity and neurotoxic potential including effects of CCL11 and CCL2 were significantly increased in MNP. A large part of the variance in PHEM (38.4-52.6%) and negative (65.8-74.4%) symptoms were explained by combinations of immune markers whereby CCL11 was the most important. The same markers explained a large part of the variance in the Mini-Mental State examination, list learning, digit sequencing task, category instances, controlled word association, symbol coding, and Tower of London. Partial least squares analysis showed that 72.7% of the variance in overall severity of schizophrenia was explained by the regression on IL-1ß, sIL-1RA, CCL11, TNFα, and education. It is concluded that the combination of the abovementioned markers defines MNP as a distinct neuroimmune disorder and that increased immune neurotoxicity determines memory and executive impairments and PHEMN symptoms as well.

A Brief History of Immunological Research into Psychosis and Pathways for Immune Influence of the Brain.

Infection and inflammation resulting from a malfunctioning of the immune system have been discussed as pathological factors in psychosis for more than 130 years. The first immune-modulating therapeutic approaches for psychosis were developed more than 100 years ago, but the breakthrough of antipsychotic treatment in the 1950s shifted the emphasis of research to catecholaminergic neurotransmission. In the 1990s, however, the unsatisfactory therapeutic effects of antipsychotics, and the fact that the pathological mechanisms of psychosis were still unknown, reignited the scientific interest in other topics, including inflammation. In parallel, the further development of immunological methods enabled a more sophisticated examination of immunological and inflammatory mechanisms. Psychiatrists' interest in this interdisciplinary field increased as a consequence of encouraging results of psychoneuroimmunological research and broader funding of the field. In the meantime, the benefits of anti-inflammatory treatment in psychosis have been demonstrated in clinical studies and meta-analyses. Future studies are warranted to evaluate the exact immunological mechanisms in the pathophysiology of the disease, optimize the anti-inflammatory treatment approach and develop more targeted, personalized therapies in psychosis.

Autoantibodies and Psychosis.

Research into antibody-mediated disease, in response to immune dysfunction or to tumour development, has rapidly expanded in recent years. Antibodies binding to neuroreceptors can cause psychiatric features, including psychosis, in a minority of patients as well as neurological features. The responsiveness of some of these cases to immunotherapy supports the hypothesis that antibody-associated mechanisms play a role in the pathogenesis of psychotic diseases. The purpose of this chapter is to review autoantibodies that are most likely to be relevant for patients with psychotic symptoms. Herein, we describe receptor structure and mechanism of action, clinical and psychiatric features for the growing number of neuronal surface antibodies, including those to the N-methyl-D-aspartate (NMDA) receptor. The identification of a subgroup of patients with psychiatric features having antibody-mediated disease highlights the importance of considering the diagnosis, particularly in those patients presenting with a first episode of psychosis.