Disrupted relationship between blood glucose and brain dopamine D2/3 receptor binding in patients with first-episode schizophrenia.

An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behavior, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signaling in drug-naïve patients with first-episode psychosis. We quantified blood glucose levels and binding of the dopamine D2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naïve patients and 27 healthy volunteers employing positron emission tomography. Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. We observed positive relationships between blood glucose levels and binding-potential values in healthy volunteers but negative ones in patients with first episode psychosis in a cluster surviving rigorous multiple testing correction located in the in the right ventral tegmental area. Another cluster of homologous behavior, however at a lower level of statistical significance, comprised the ventral striatum and pallidum. Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signaling occurs when goal-directed behavior is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are high when blood glucose levels are low and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting an underlying pathogenic alteration that links two seemingly unrelated aspects of the illness: altered dopamine signaling and dysfunctional glucose homeostasis.

Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study.

OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

Clinical correlates of augmentation/combination treatment strategies in major depressive disorder.

OBJECTIVE: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). METHOD: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. RESULTS: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. CONCLUSION: Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities.

[The capacity of fusicoccin for inducing the synthesis of early interferon].

The response of human and animal cells to the action of fusicoccin (FC), a fungal metabolite with phytohormonal properties, was evaluated. The capacity of FC for inducing the synthesis of early interferon (IFN), supplied into the blood serum of common white mice, and for enhancing the natural cytotoxic activity of human lymphocytes in vitro was established. The metabolism of actively proliferating monocytic leukemia cells J-96 and human ovarian carcinoma cells CaOv, as well as mouse fibroblasts L-929, was found to be inhibited under the in vitro action of FC. The common character of the mechanisms of action of FC and IFN having antiproliferative and immunomodulating activity is discussed.

[Capacity of fusicoccin for inducing the production of early interferon].

The response of human and animal cells to the action of fusicoccyne (FC), a fungal metabolite with phytohormonal properties, was evaluated. As shown by in vitro studies, FC had the capacity to induce the production of early interferon (IFN) in the blood serum of non-inbred white mice and to enhance the natural cytotoxic activity of human lymphocytes. In vitro experiments also revealed that the action of FC inhibited the metabolism of actively proliferating monocytic leukemia cells J-96 and human ovarian carcinoma cells CaOv, as well as mouse fibroblasts L-929. The common character of the mechanism of action of FC and IFN, having well-known antiproliferative and immunomodulating activity, is discussed.

Endogenous fusicoccin-like ligand revealed in higher plants by radioreceptor and radioimmunoassays.

Radioimmuno- and radioreceptor assays were developed for quantitating fusicoccin-like substances in plants. FC-like ligands were found in cultured horseradish roots (70-90 pmol/g) and headed cabbage leaves (9-11 pmol/g). Detection of FC-like ligands in sterile root culture further argues in favour of endogenous fusicoccin representing a new type of phytohormone.

[Level of R-proteins in blood during development of diabetes mellitus]. / Uroven' R-belkov v krovi pri razvitii sakharnogo diabeta.

R-proteins were studied in children with diabetes mellitus and in the risk group. The highest titre of the pattern was found in the children group where diabetes was the first to be detected. Normalization of the R-proteins high titre after insulin therapy was more typical for patients with first detected diabetes as compared with children impaired by the disease within 1-2 years. Content of immunoreactive insulin and titre of R-proteins correlated in the risk group. Estimation of the R-proteins titre simultaneously with other markers may be used for early diagnosis of diabetes mellitus as well as in control of the disease compensation.

Herpes simplex virus antibodies in the cerebrospinal fluid of schizophrenic patients.

Antibodies to herpes simplex virus type 1 (HSV-1) were tested in the cerebrospinal fluid (CSF) of 262 schizophrenic patients by virus neutralization test (VNT) and enzyme-linked immunosorbent assay (ELISA). While VNT in the presence of complement revealed antibodies to HSV-1 in 18.3% of samples, ELISA was positive in 61.2% of cases; both tests were positive in 42 samples (16%).

[The role of A-cells in affecting the immunostimulating effect of F(ab')2-fragments]. / Rol' A-kletok v realizatsii immunostimuliruiushchego deistviia F(ab')2-fragmentov.

The immunoregulatory effect of F(ab')2 fragments on normal rabbit IgG and that preincubated with A-cells from spleen have been compared. Both products were tested for their ability to enhance primary immune response of rabbit spleen cells to SRBC. It was demonstrated that low molecular mass product appeared after F(ab')2 fragments incubation with A-cells at 37 degrees C and possessed immunostimulating activity similar to that of initial F(ab')2 fragments. In addition, it was shown that F(ab')2 reduction to monovalent Fab' fragment with the following alkylation of SH-group abolished the ability of Fab' fragment to enhance the immune response. It may signify that half cystein Fab' fragment residue is essential for processing of the fragment in A-cells and (or) for immune response enhancement.

Studies of Fc receptors of heart valve and joint fibroblasts.

Normal human and rabbit sera, and the IgG isolated from them, have been shown by immunofluorescence to react with bovine and human heart valve fibroblasts. Analogous results were obtained with sera of children under the age of 2. Positive reactions were observed also with fibroblasts, chondrocytes and osteocytes of human fetal joint tissues. The reactions are mostly due to monomeric immunoglobulins, since soluble immune complexes give much weaker reactions with the fibroblasts. The reactions are apparently dependent on the presence of Fc receptors on these cells. This conclusion is confirmed by positive reactions with IgG Fc fragments, with pure antibodies to ovalbumin and with human monoclonal IgG. The monoclonal IgG1 possesses the strongest ability to bind with fibroblast Fc receptors. No Fc-IgG receptors have been revealed on the fibroblasts and other structures of the interstitial connective tissue of human and bovine myocardium.

[Differences in the properties of antibodies and natural antiglobulin-homoreactants revealed by the method of human IgG chemical modification]. / Ispol'zovanie metoda khimicheskoi modifinkatsii IgG cheloveka dlia dokazatel'stva razlichiia v svoistvakh antitel i estestvennykh antiglobylinovgp, prealtamtpv.

The naturally occurring antiglobulin factors - homoreactants, contained by human IgG preparations, are inactivated as a result of incubation in a solution of sodium rhodanide (3 - 5 M) and sodium desoxycholate (0.005M). Staphylococcal antitoxin contained by the same human IgG preparations is resistant to the action of the reagents. The data obtained indicate the differences in the structure of homoreactants and antibodies.

[Reactions of normal human and rabbit immunoglobulins with heart valve fibroblasts]. / Reaktsii normal'nykh immunoglobulinov cheloveka i krolika s fibroblastami klapanov serdtsa.

It was demonstrated using the indirect immunofluorescent technique that normal human and rabbit sera, and IgG isolated from them intensively reacted with fibroblasts of human and bovine heart valves. The results obtained with Fab and Fc fragments of IgG sugges that this reaction is due to the Fc region of the IgG molecule and related to the presence of the Fc receptor on fibroblasts of heart valves.

Further studies of the adjuvant properties of homologous IgG split products: mode of action of F(ab')2 and related fragments.

Peptic bivalent and monovalent Fab' fragments as well as F(ab')2 fragment from a purified rabbit anti-DNP antibody were equally effective in enhancement of the immune response to SRBC. In contrast, the papain Fab fragment of normal IgG possessed a considerably lower enhancing activity. These data indicate that the effector site(s) controlling the adjuvant activity of F(ab')2 and related fragments is structurally distinct from the antibody active site(s) within the fragment molecule, and is located in C-terminal region of the heavy chain Fd fragment. When F(ab')2 fragment was injected into rabbits together with the proteinase inhibitor Trasylol it failed to enhance the immune response to SRBC. Furthermore, Trasylol interferes with the ability of F(ab')2 or Fab' fragment to activate the complement system both in vivo and in vitro. This, together with the observation that F(ab')2 fragments enhance the response to T-dependent antigens (SRBC and bovine gamma globulin) but fail to augment the response to LPS, suggests that these fragments may operate via activation of complement and thereby influence indirectly the reactivity of complement receptor B cells.