[Long-term maintenance therapy of depressive disorders with antidepressants: experience of using agomelatin]. / Dlitel'naya podderzhivayushchaya terapiya depressivnykh rasstroistv antidepressantami: opyt primeneniya agomelatina.

The article presents the literature data that determine the place of antidepressants in the relief and maintenance therapy for recurrent depression (RD) and depression in the framework of bipolar affective disorder (BPAD) and provides a justification for their use in the presence of residual depressive symptoms during remission. There are several ways to achieve complete remission: determination of the nature of residual symptoms; identification of adverse side-effects that have occurred as a result of the therapy; the establishment of those symptoms that are subjectively perceived by the patient as interfering with his/her full life. The data on the effective use of agomelatin for maintenance therapy, both as monotherapy and in combination with other antidepressants, anticonvulsants and neuroleptics, in RD and BPAD are presented. The authors have analyzed the case histories of 29 outpatients with depressions of various origins (RDD, BPAD, prolonged psychogenic depression, organic affective disorder), who received agomelatin as part of complex and monotherapy for a long time (1 to 13 years), and justified the predictors of its efficacy.

Senescence and entrenchment in evolution of amino acid sites.

Amino acid propensities at a site change in the course of protein evolution. This may happen for two reasons. Changes may be triggered by substitutions at epistatically interacting sites elsewhere in the genome. Alternatively, they may arise due to environmental changes that are external to the genome. Here, we design a framework for distinguishing between these alternatives. Using analytical modelling and simulations, we show that they cause opposite dynamics of the fitness of the allele currently occupying the site: it tends to increase with the time since its origin due to epistasis ("entrenchment"), but to decrease due to random environmental fluctuations ("senescence"). By analysing the genomes of vertebrates and insects, we show that the amino acids originating at negatively selected sites experience strong entrenchment. By contrast, the amino acids originating at positively selected sites experience senescence. We propose that senescence of the current allele is a cause of adaptive evolution.

Contributions of anterior cingulate cortex and basolateral amygdala to decision confidence and learning under uncertainty.

The subjective sense of certainty, or confidence, in ambiguous sensory cues can alter the interpretation of reward feedback and facilitate learning. We trained rats to report the orientation of ambiguous visual stimuli according to a spatial stimulus-response rule that must be learned. Following choice, rats could wait a self-timed delay for reward or initiate a new trial. Waiting times increase with discrimination accuracy, demonstrating that this measure can be used as a proxy for confidence. Chemogenetic silencing of BLA shortens waiting times overall whereas ACC inhibition renders waiting times insensitive to confidence-modulating attributes of visual stimuli, suggesting contribution of ACC but not BLA to confidence computations. Subsequent reversal learning is enhanced by confidence. Both ACC and BLA inhibition block this enhancement but via differential adjustments in learning strategies and consistent use of learned rules. Altogether, we demonstrate dissociable roles for ACC and BLA in transmitting confidence and learning under uncertainty.

[Bipolar affective disorder: gender differences in the course and treatment]. / Bipoliarnoe affektivnoe rasstroistvo: gendernye osobennosti techeniia i terapii.

Bipolar affective disorder (BAD) according to the latest international classifications (ICD-10, DSM-5) is recognized as its own disease, characterized by episodes of mania (or hypomania), hyperthymic personality and (or) a genetic predisposition to BAR in contrast to recurrent depressive disorder (RD). The history of development and classification of manic depressive disorder (MDD), difficulties of differential diagnosis between BAD and RD are presented in this literature review. It considers the clinical features of the course of BAR in men and women and also gender-specific therapy. Gender differences in the clinical picture, course and treatment of BAD are discussed. Attention is drawn to the differences in effectiveness and tolerability of antidepressants in men and women. It is concluded that identifying the gender particularities is important for treatment and prevention optimization.

[The effect of the biologically active additive epiphamine on antioxidant and NADPH-generating enzymes activity under experimental cerebral ischemia/reperfusion in rats]. / Vozdeistvie BAD épifamin na aktivnost' antioksidantnykh i NADPH-generiruiushchikh fermentov pri éksperimental'noi ishemii/reperfuzii golovnogo mozga u krys.

The effect of biologically active additive with immunomodulator properties epiphamine on the activity of antioxidant (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase) and NADPH-generating (glucose-6-phosphate dehydrogenase, NADP-isocitrate dehydrogenase) enzymes has been investigated at experimental cerebral ischemia/reperfusion in rats. The results obtained indicate epiphamine-induced changes of these enzymes activities towards control values. Changes in the content of lactate, a marker of the pathology development, have also been found in experimental animals under ischemia and epiphamine administration caused changes similar to those observed in the case of enzyme activities studied. In most cases, the changes were dose-dependent. Thus, epiphamine can be of considerable interest from the point of view of metabolic changes pharmacological correction at the development of the pathology accompanied by oxidative stress.

[The effect of melaxen administration on the tissue oxidative status in rats with brain ischemia/reperfusion]. / Oksidativnyi status tkanei krys pri vvedenii melaksena na fone razvitiia ishemii/reperfuzii golovnogo mozga.

Melaxen administration to rats with brain ischemia/reperfusion was accompanied by a decrease of the lactate level (an organ ischemia marker), biochemiluminescence parameters characterizing the intensity of free radical processes and total antioxidant activity, the content of lipid peroxidation products, activity of superoxide dismutase and catalase, as compared with the values determined in rats with induced brain ischemia/reperfusion. Activity of aconitate hydratase, a sensitive target of free radicals action, and the citrate level in the brain and blood serum of melaxen-treated animals changed towards control values of intact animals. It is assumed that the effect of melaxen is associated with implementation of the antioxidant and protective properties of melatonin, the melaxen constituent, under conditions of post-ischemic reperfusion injury, accompanied by oxidative stress development.

[Investigation of the mechanism of bivalent iron binding by casein phosphopeptides].

The article presents the results of investigations of mechanism of binding (chelation) of iron by casein phosphopeptides (CPPs). Molecular mass distribution of peptides in the form of the aqueous solutions of casein phosphopeptides, obtained by enzymatic hydrolysis of sodium caseinate by various proteinases has been studied. The greatest number of low-molecular peptides with molecular weight less than 2.8 kDa has been detected in the trypsin hydrolysate. Peptic and chymotryptic hydrolysates have similar qualitative composition and contain peptides with higher molecular weight. Under chymosin hydrolysis of sodium caseinate, mainly peptides with high molecular weight were formed, and fragments with molecular weight less than 2.8 kDa were not detected. In the study of chelating ability of CPPs it has been found that the maximum amount of iron was bound by peptide fraction of trypsin hydrolysate. Iron content in peptide complexes of trypsin hydrolysate was 18.8 mg/g of protein, and in those of himotrypsin hydrolysate and pepsin hydrolysate - 13.2 and 11.3 mg/g protein, respectively. It was noted that with increasing doses of iron, the degree of chelation of this micronutrient in all hydrolysates reduced. Chromatographic studies have shown that more than 70% of chelated iron in pepsin and trypsin hydrolysates, was found in peptide fractions with a molecular weight of 0.5-1.4 kDa and only 30% in fractions with a molecular weight of 1.4-4.5 kDa. Amino acid profiles of CPPs peptides have been studied in trypsin hydrolysate by using mass-spectroscopy. It was found that after the interaction of amino acids with iron the value of molecular ion peaks on the plots -Val-Ser-Ser-Glu-Glu-, and -Ala-Glu-Ser-Ser-Ser-Glu- Glu- increased by 15-25%, indicating the binding of these amino acids with the metal. The data obtained showed that most of the iron was associated with low molecular weight fraction of relatively short peptides of molecular weight from 1.4 to 4.5 kDa. It was noted that enzymatic hydrolysis of sodium caseinate by trypsin produced the greatest amount of low molecular weight peptides that bond iron and increased its bioavailability. It should be noted that chelated complexes are easy to penetrate into the cells, freeing the metal exactly where it is needed, protecting it from oxidation and interaction with other elements in the gastrointestinal tract. The results obtained allowed to optimize the nutrient medium and to provide high chelation of iron.