Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis.
TL;DR: Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies and the repertoire of antibody subtypes in schizophrenia and MD is different from that with NMda-R encephalitis.
Abstract: Context: Evidence for symptomatic convergence of schizophrenia and N-methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. Objectives: To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap withanddistinctionfromthoseinNMDA-Rencephalitis. Design: Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or individuals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and -amino-3-hydroxyl-5-methyl-4-isoxazole-propionatereceptors(AMPA-R)(GluR1/GluR2)serumantibodieswere determined. Participants:Twohundredthirtymatchedhealthycontrols were compared with patients (unmedicated for at least6weeks)withschizophrenia(n=121),MD(n=70), or BLPD (n=38). Main Outcome Measures: The primary outcome was theoverallnumberofseropositivecasesforNMDA-Rand AMPA-R antibodies; the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. Results: Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classifiedashavingcatatonicordisorganizedschizophreniawere reclassified as having misdiagnosed NMDA-R encephalitis(presenceofspecificserumandcerebrospinalfluidIgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directedagainstNR1a/NR2b(notagainstNR1aalone).None ofthepatientsorcontrolshadantibodiesagainstAMPA-R. Conclusions: Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypesinschizophreniaandMDisdifferentfromthatwith NMDA-Rencephalitis.Thelatterdisordershouldbeconsidered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.
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Verneri Anttila1, Verneri Anttila2, Brendan Bulik-Sullivan2, Brendan Bulik-Sullivan1 +717 more•Institutions (270)
TL;DR: It is demonstrated that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine, and it is shown that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures.
Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.
1,357 citations
TL;DR: The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum, and antibody titres were higher in patients with poor outcome than in those with good outcome, emphasising the importance of including CSF in antibody studies, and that antibody titre can complement clinical assessments.
Abstract: Summary Background Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with anti-NMDA receptor encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with anti-NMDA receptor encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA receptor mutants. Findings We analysed samples from 250 patients with anti-NMDA receptor encephalitis and 100 control participants. All 250 patients had NMDA receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.
710 citations
TL;DR: Some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, it is thought, will be of interest to psychiatric clinicians and researchers are described.
586 citations
TL;DR: Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy, and future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
Abstract: The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
418 citations
TL;DR: The process of discovery of these diseases is traced, describing the triggers and symptoms related to each autoantigen, and the structural and functional alterations caused by the autoantibodies are reviewed with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals.
Abstract: Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all...
394 citations
References
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11 Jun 2013
113,134 citations
Journal Article•
TL;DR: The Mini-International Neuropsychiatric Interview is designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings.
Abstract: The Mini-International Neuropsychiatric Interview (M.I.N.I.) is a short structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States and Europe, for DSM-IV and ICD-10 psychiatric disorders. With an administration time of approximately 15 minutes, it was designed to meet the need for a short but accurate structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be used as a first step in outcome tracking in nonresearch clinical settings. The authors describe the development of the M.I.N.I. and its family of interviews: the M.I.N.I.-Screen, the M.I.N.I.-Plus, and the M.I.N.I.-Kid. They report on validation of the M.I.N.I. in relation to the Structured Clinical Interview for DSM-III-R, Patient Version, the Composite International Diagnostic Interview, and expert professional opinion, and they comment on potential applications for this interview.
19,347 citations
"Increased prevalence of diverse N-m..." refers methods in this paper
...Patients with a history of immune diseases, immunomodulating treatment, cancer, chronic terminal disease, cardiovascular disorders, diabetes mellitus, substance abuse, and severe trauma or clinical/paraclinical findings indicating these disorders were excluded, and controls were screened for personal or family history of neuropsychiatric disorders using the MiniInternational Neuropsychiatric Interview.(32) Blood was collected between 8 and 9 AM (fasted, 2-hour clotted)....
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...Patients with a history of immune diseases, immunomodulating treatment, cancer, chronic terminal disease, cardiovascular disorders, diabetes mellitus, substance abuse, and severe trauma or clinical/paraclinical findings indicating these disorders were excluded, and controls were screened for personal or family history of neuropsychiatric disorders using the MiniInternational Neuropsychiatric Interview.32 Blood was collected between 8 and 9 AM (fasted, 2-hour clotted)....
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TL;DR: These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
Abstract: Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
3,166 citations
Additional excerpts
...It has been suggested that the profile of symptoms in NMDA-R encephalitis depends on the intensity of the antibody effects on the density of NMDA-R,(17) which is similar to observations after ketamine hydrochloride and phencyclidine hydrochloride administration.(18,19) Low doses of these NMDA-R antagonists cause psychosis, anxiety, agitation, memory disturbance, decreased responsiveness to pain, and speech reduction, whereas higher doses produce dissociative anesthesia, a state of profound unresponsiveness with catatonic features, orofacial and limb dyskinesias, autonomic instability, and seizures....
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TL;DR: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP and the findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia.
Abstract: Objective: Phencyclidine (PCP, “angel dust”) induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding ofschizophrenic pathophysiology. Methoc�: Twenty-five papers were identified that described the clinicaldose and serum and CSF levelsat which PCP induces its psychotomimetic effects. The dose range ofPCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. Results: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation ofits receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. Conclusions: These findings suggestthat endogenous dysfunction ofNMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models ofschizophrenia are discussedin relationship to the diagnosis and etiology of schizophrenia. (Am J Psychiatry1991;148:1301-1308)
2,883 citations
"Increased prevalence of diverse N-m..." refers background in this paper
...Low doses of these NMDA-R antagonists cause psychosis, anxiety, agitation, memory disturbance, decreased responsiveness to pain, and speech reduction, whereas higher doses produce dissociative anesthesia, a state of profound unresponsiveness with catatonic features, orofacial and limb dyskinesias, autonomic instability, and seizures.(17,20,21) Interestingly, Zandi et al(22) observed NMDA-R serum antibodies in approximately 6% (3 of 46 patients) with firstonset schizophrenia....
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Book•
01 Jan 2002
TL;DR: "Dementia Praecox and Paraphrenia" (1919) was the book in which Kraepelin first presented his work on schizophrenia to the English-speaking world, and it was probably the most influential psychiatric text of the entire 20th century, and has now become rare.
Abstract: The German psychiatrist Emil Kraepelin (1856 - 1926) is justly called "the father of modern psychiatry". He was the first to identify dementia praecox (schizophrenia) and manic-depression, and he pioneered the use of drugs to treat mental illness. He was also joint discoverer of Alzheimer's disease - which he named after his collaborator, Dr Alois Alzheimer. Kraepelin presented these and other discoveries in successive editions of his "Psychiatrie: Ein Lehrbuch" (definitive 8th edition also now available from Thoemmes Press). Much of this gigantic textbook can only be read in the original German; but parts of it were translated into English, and they had a very profound influence on the development of world psychiatry for the rest of the 20th century. Although Bleuler's name for the disease "schizophrenia" came to replace Kraepelin's term, Kraepelin's general description of the syndrome and division of it into subforms such as hebephrenia and catatonia has persisted. He succeeded in tying together into a single recognizable diagnostic category a disparate array of symptoms that, before Kraepelin, had not been seen as cohering. Despite myriad later refinements, Kraepelin's description of the syndrome is still the classic presentation; it very much lives on in the "Diagnostic and Statistical Manual" used by present-day psychiatrists. "Dementia Praecox and Paraphrenia" (1919) was the book in which Kraepelin first presented his work on schizophrenia to the English-speaking world. It was probably the most influential psychiatric text of the entire 20th century, and has now become rare. Thoemmes Press is pleased to make this facsimile of the first edition available as a single volume.
2,825 citations
"Increased prevalence of diverse N-m..." refers background in this paper
...Thus, the increased prevalence of IgA NMDA-R antibodies in the schizophrenia cohort suggests an immunological link to Emil Kraepelin’s “dementia praecox” concept.(39) This idea may be clarified in future studies by providing additional cognitive test data from patients seropositive for IgA NMDA-R antibodies....
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