BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year.

Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs.

Antibodies to surface dopamine-2 receptor and N-methyl-D-aspartate receptor in the first episode of acute psychosis in children.

BACKGROUND: The dopamine and glutamate hypotheses are well known in psychosis. Recently, the detection of autoantibodies against proteins expressed on the surface of cells in the central nervous system has raised the possibility that specific immune-mediated mechanisms may define a biological subgroup within psychosis, although no cohort of a first episode of psychosis in children has been investigated. METHODS: Serum taken during the acute presentation of 43 children with first episode of psychosis and serum from 43 pediatric control subjects was assessed for the presence of immunoglobulin (Ig)G, IgM, or IgA antibodies to dopamine-2 receptor (D2R) and NR1 subunit of the N-methyl-D-aspartate receptor using a flow cytometry live cell-based assay and immunolabeling of murine primary neurons. RESULTS: Using a cutoff of three SD above the control mean, serum antibodies to D2R or NR1 were detected in 8 of 43 psychotic patients but not detected in any of 43 control subjects (p < .001). Positive immunoglobulin binding to D2R was found in 3 of 43 psychosis patients (3 IgG, 1 IgM, 0 IgA) and to N-methyl-D-aspartate receptor in 6 of 43 patients (5 IgG, 1 IgM, 1 IgA). Specificity of antibody was confirmed by immunoaffinity purification and immunoabsorption. Significant differences in antibody binding to live, fixed, and fixed and permeabilized neurons were observed, confirming that only live cells can define surface epitope immunolabeling. CONCLUSIONS: This is the first report of serum antibodies to surface D2R and NR1 in pediatric patients with isolated psychosis, which supports the hypothesis that a subgroup of patients may be immune-mediated.

[The state of the immune system in endogenous mental diseases with pronounced affective disorders].

Parameters of innate and adaptive immunity were studied in the blood serum of 180 patients, aged 15-25 years, with different endogenous mental diseases with depressive and mania disorders in the clinical picture (affective psychoses (29 patients), schizoaffective psychoses (106 patients) , slow-progressive schizophrenia (23 patients) and intermittent-progressive schizophrenia (22 patients)). The activation of innate immunity (the increase in the degranulation activity of leukocyte elastase (LE) and functional activity of alpha-1-proteinase inhibitor (α1-PI) were found in all the diseases. The increase in disease severity (from affective disorders to intermittent-progressive schizophrenia) was correlated with the significant elevation of LE activity. The LE activity did not depend on the polarity and severity of affective pathology in each diagnostic group. The mean levels of autoantibodies to the nerve growth factor and the myelin basic protein did not differ from the control values in all the groups of patients.

Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders.

Recent studies suggest inflammatory mechanisms involved in the pathogenesis of major psychiatric disorders (MPD). T cells play a major role during inflammation, but little is known about T cell subpopulations in the cerebrospinal fluid (CSF). We investigated the frequency of cells positive for the surface markers CD4, CD8, CD25, CD45, CD69, and CD127 in 45 paired cerebrospinal fluid (CSF) and peripheral blood (PB) samples by multiparameter flow cytometry from patients with MPD of the schizophrenic and affective spectrum with normal CSF cell counts and compared them with those from patients with non-inflammatory (NIND), chronic inflammatory (CIND) neurological disorders, and meningitis (MEN). In MEN patients, CD4+ cell frequency in PB, but not in CSF, was significantly increased as compared to CIND and NIND. No difference between patient groups was observed for CD8+. CD4+CD45RO+ double positive cells in PB were significantly lower in CIND than in MEN or NIND. The frequency of CD4+CD25+ cells in PB was significantly higher in MEN than in MPD or CIND. For CSF, the percentage of CD4+CD127(dim) cells was significantly lower in MEN than in MPD. CD4+CD127(dim) in PB and CSF showed overlapping characteristic clusters between MPD and CIND and MEN patients. Overall, the hypothesis of low degree inflammation in a subgroup of MPD is supported. The analysis of lymphocyte subsets in PB and CSF constitutes a novel promising tool to understand underlying pathomechanisms in psychiatric and neurological disorders on an individual case level.

[The effect of dalargin on the opioid and immune systems in patients with a depressive syndrome]. / Vliianie dalargina na opioidnuiu i immunnuiu sistemy bol'nykh s depressivnym sindromom.

Depressed patients and healthy donors received dalargin. As shown by the radioreceptor test, the patients recovered normal quantitative and qualitative values of plasma opioid activity due to this drug which is a synthetic agonist of sigma-type opioid receptors. Lymphocyte proliferative activity (spontaneous and induced by polyclonal mitogens) was not significantly different in the test subjects versus the donors, though in vitro studies revealed multidirectional homeostatic effects of dalargin. It is shown that depressions are associated with defective relationships between functions of the immune and opioid system. Dalargin proved uneffective in the treatment of endogenic psychotic depressions, whereas in reactive neurotic depressions and psychosomatic abnormalities the drug is promising and needs further investigations.

Factors related to the presence of autoantibodies in patients with chronic mental disorders.

Serum samples from 307 patients with various chronic mental disorders were examined for the presence of several autoantibodies. Autoantibodies detected included antinuclear antibodies (ANA) in 122/307 (39.7%), rheumatoid factor (RF) in 23/307 (7.5%), anticardiolipin antibodies (anti-CL) in 23/304 (7.6%, IgM in 12 patients, IgG in 13 patients). Isolated cases with IgG anti-dsDNA, anti-Ro(SSA), and anti-Ro(SSA)/anti-La(SSB) were also identified. The analysis of data revealed that the aging process in patients studied contributed significantly to the incidence of ANA (p less than 0.0001) and RF (p less than 0.01). In addition, the chronic administration of chlorpromazine (CPZ) was associated with the presence of ANA (p less than 0.03) as well as with the presence of IgM and/or IgG anti-CL antibodies (p less than 0.003). Finally, the diagnosis of schizophrenia correlated with the presence of ANA (p less than 0.001). This study represents the autoantibody profile of patients with chronic mental disorders and emphasizes the multifactorial origin of autoantibody response in psychiatric patients.

[Immunologic characteristics of patients with reactive depressions]. / K immunologicheskoi kharakteristike bol'nykh reaktivnymi depressiiami.

The authors examined 82 patients suffering from reactive depressions with a relatively acute, subacute and protracted course, 10 patients with a reactive onset of schizophrenia and 24 normal subjects. The test subjects were examined over time for titres of heterohemolysins, S-RB, antibodies against cerebral antigens and the administered drugs as well as for relative parameters of T- and B-rosettes. The results obtained make it possible to identify the most frequent combinations of the examined parameters in the above groups of patients with various symptomatology. Immunological indices may be an important criterion for selecting the therapy of patients with reactive depressions. Thus the detection in the serum of antibodies against the administered drugs may serve as a sufficient basis for changing the therapy and using medicaments of a different chemical structure.

Prediction of affective psychoses response to lithium prophylaxis. The role of socio-demographic, clinical, psychological and biological variables.

A set of socio-demographic, clinical, psychological and biological variables was examined in 100 patients diagnosed according to Perris as bipolar affective psychotics or unipolar depressive psychotics, maintained on prophylactic lithium for 2 years and divided into responders and non-responders to this treatment on the basis of strict criteria. The results confirmed the potential role of four indices as predictors of response to prophylaxis: a positive family history of bipolar affective illness and a high red blood cell/plasma lithium ratio (positive predictors) and the presence of the HLA-A3 antigen and a high score on the Neuroticism Scale of the Eysenck Personality Questionnaire (negative predictors). A stepwise discriminant analysis showed that neuroticism score, lithium ratio and HLA-A3 antigen, taken together, correctly classified 74.6% of responders and 68.3% of non-responders. It is hypothesized that these variables as a group may be of practical value in predicting response to lithium prophylaxis, and that pharmacogenetic and, perhaps, personality factors may be involved in treatment failures.

Antibodies to Epstein-Barr virus, herpes simplex type 1, cytomegalovirus and measles virus in psychiatric patients.

Distribution of antibodies to herpes simplex type 1 (HSV1), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and measles virus (MV) was studied in sera and cerebrospinal fluids (CSF) of 41 patients with schizophrenia, 27 patients with primary affective disorders and 25 control patients with neurological diseases. No significant differences in distribution and mean geometric titers (GMT) of antibodies to HSV1 between the psychiatric and control groups were found. Distribution and GMT of antibodies to EBV were highly significant in psychiatric patients as compared to controls with highest titers in the affective disorder group. Antibodies to HSV1 were present in 15 CSF specimens of psychiatric patients with reduced CSF/serum ratio in 4, and low levels of antibodies were detected in 8 control patients. Antibodies to EBV-VCA were detected in 4 CSFs of psychiatric patients. Total protein levels were determined in CSF specimens and no correlation with antibodies was found. No significant differences in distribution of antibodies to CMV or MV in the three study groups were found. No antibodies to CMV were demonstrated in CSFs and in one specimen from a patient and two controls antibodies to MV were detected.

Antibody and cell-mediated immunity to herpes simplex virus in psychotic depression.

The incidence and antibody titers to herpes simplex virus (HSV) were found significantly higher in patients with psychotic depression as compared to normal controls. Furthermore, the cell-mediated immunity (CMI) to HSV in psychotic depression was similar to that observed after acute HSV infection or recurrence. The results suggest therefore an association between HSV infection and psychotic depression.