Biomarkers of Systemic and Neuronal Autoimmunity in Acute Psychiatric Disorders

Abstract

Summary: Introduction and aims: Patients with autoimmune disorders with autoantibodies against systemic and neuronal targets frequently present with neuropsychiatric symptoms. The literature on the prevalence and clinical significance of these autoantibodies in acute psychiatric disorders is limited, however. This thesis aims at investigating the prevalence of autoantibodies directed to systemic and neuronal targets in patients admitted to acute psychiatric inpatient care, the assumption being that these autoimmune biomarkers might be more prevalent in patients with affective and psychotic disorders as compared to those with other acute psychiatric presentations. In addition, the thesis includes a systematic review of the existing literature on the significance of onconeural antibodies for psychiatric symptomatology. Methods: Serum was drawn from patients admitted to acute psychiatric inpatient care during 2004-06 (Cohort 1, n=585) and 2011-12 (Cohort 2, n=340). Psychiatric diagnoses were set according to International Classification of Diseases (ICD)-10 criteria. Patients from both cohorts were screened for the presence of Immunoglobulin (Ig)G, IgA and IgM autoantibodies directed to six neuronal membrane/synaptic targets (including N-methyl D-aspartate receptor (NMDAR), contactin-associated protein-like 2 (CASPR2), and glutamic acid decarboxylase-65 (GAD65)). In addition, patients from cohort 1 were screened for onconeural antibodies (e.g. Hu, Yo, and Ma2 antibodies) and autoantibodies directed to systemic and organ-specific targets (e.g. antinuclear (ANA) and thyroid peroxidase (TPO) antibodies). In the systemic review, we evaluated studies describing the psychiatric symptomatology of onconeural antibody positive patients and the prevalence of onconeural antibodies in patients with psychiatric disorders. Results: Autoantibodies directed against neuronal membrane/synaptic targets were found in 107out of 925 patients (11.6%) in our cohorts. The most frequent antibodies were directed against NMDAR (7.6%), CASPR2 (2.5%), and GAD65 (1.9%). NMDAR IgG antibodies were present in five patients only (0.5%). There were no significant differences in antibody prevalence in the different ICD-10 diagnostic categories, except for a higher odds ratio of being NMDAR antibody positive for patients who did not fulfill ICD-10 criteria for a specific psychiatric diagnosis. NMDAR antibodies of all Ig classes were equally prevalent in patients with and without psychosis. Onconeural antibodies were detected in one out of 585 patients (0.2%). This patient were diagnosed with paranoid psychosis and tested positive to anti-recoverin. Autoantibodies against systemic and organ-specific targets were present in 153 out of 585 patients (26.2%). The most prevalent antibodies were ANA (9.4%), rheumatoid factor (RF) (9.2%) and anti-TPO (5.6%). Autoantibody prevalence increased with age (OR 1.21, 95% CI 1.09-1.35) and smoking status (OR 1.99, 95% CI 1.04-3.82), but was not associated with a diagnosis of a psychotic or affective disorder. Twenty-seven studies met the inclusion criteria for the systematic review, but only six studies included data on the prevalence of onconeural antibodies in patients with psychiatric disorders. Onconeural antibodies in the cerebrospinal fluid of patients with psychotic and depressive syndromes were assessed in two studies. The prevalence of onconeural antibodies in patients with psychiatric disorders was low (<5.0%). Conclusions: Patients with psychotic and affective disorders do not seem to have an increased prevalence of systemic and neuronal autoantibodies as compared to patients with other acute psychiatric presentations. Our negative findings do not necessarily suggest that autoantibodies are insignificant for patients with psychiatric disorders. Instead, it might be that traditional psychiatric diagnostic classifications such as the DSM-IV are inadequate for the plethora of autoimmune psychiatric symptoms. Future research should therefore evaluate the clinical significance of autoantibodies in psychiatric patients without stratifying patients into standard psychiatric diagnoses. Such studies should be longitudinal in design and include thorough investigation for psychiatric and organic phenotypes.

Sammendrag: Det har lenge vore kjend at immunsystemet ved nokre høve produserer protein (antistoff) som angrip kroppen sjølv (autoantistoff). Dette kan gje opphav til autoimmune sjukdomar, som for eksempel leddgikt. Dei seinare åra har ein oppdaga fleire typar autoantistoff som angrip protein på hjernecellene og fører til sjukdomar med alvorlege psykiatriske og nevrologiske symptom (som psykose, krampar og ufriviljuge rørsler). I dette doktorgradsarbeidet undersøkte eg i kor stor grad autoantistoff retta mot protein på hjerneceller og andre celler er til stade i blodet hjå menneske innlagt på akuttpsykiatrisk avdeling. Eg fann at fleire typar autoantistoff førekjem hyppig hjå desse pasientane, men fann ikkje nokon skilnad i førekomst mellom pasientar med ulike psykiske lidingar. Frå anna forsking veit vi at autoantistoffa førekjem om lag like hyppig hjå friske menneske som det vi fann i våre studiar. Det er uklart kvifor autoantistoff tilsynelatande skapar sjukdom hjå nokre menneske, men andre ikkje. Framtidig forsking bør søke å avklare om autoantistoff har ei klinisk tyding hjå menneske med psykiske lidingar eller om dei er til stades utan å gjere skade. Finn ein at autoantistoff er årsak til sjukdom for ei undergruppe av pasientar med alvorlege psykiske lidingar vil dette på sikt kunne opne for nye behandlingsmetodar. Allereie no pågår behandlingsstudiar kor ein gir immunmodulerande behandling til menneske med schizofreniliding og nokre typar autoantistoff i blodet.