[The temporal accuracy of agomelatine administration and comparison of antidepressant effect of agomelatine and escitalopram in major depression: a retrospective investigation at a psychiatric outpatient clinic]. / Az agomelatinszedés pontossága és az agomelatin-escitalopram antidepresszív hatásának összehasonlítása major depresszióban: retrospektív vizsgálat a pszichiátriai szakrendelo betegeinél.

AIM: The assessment of antidepressant efficacy of agomelatine, a new chronobiological type of antidepressant as a function of the temporal accuracy of administration, compared to the antidepressive effect of escitalopram. METHODS: In our retrospective study at the end of a 12-week treatment improvement rates were analysed in all depressed patients attending our ourpatient clinic receiving agomelatine (25 or 50 mg daily) or escitalopram (10 or 20 mg daily) monotherapy initiated between 01. 03. 2014 and 01. 03. 2015 Follow-up interviews were conducted to evaluate temporal accuracy of agomelatine administration in the evenings and we divided our group into accurately and inaccurately administered agomelatine groups. RESULTS: In the inaccurately administered agomelatine group (n=16) after 12 weeks 7 patients (43.7%) showed no improvement, 7 patients showed response (43.7%), and two entered remission (12.5%). In the accurately administered agomelatine group (n=63) 18 patients showed no improvement (28.6%), 15 were responders (23.8%) and 30 patients entered remission (47.6%). Regarding the improvement rates there was a significant difference between the two agomelatine groups (p=0.034). Comparing the 12-week improvement ratio of the accurate agomelatine group to all patients in the outpatient practice (n=62) receiving escitalopram (30 vs 29 remitters, 15 vs 15 responders, and 18 vs 18) no difference in improvement rates was shown between groups (p= 0.982). CONCLUSIONS: Our results show for the first time that the accuracy of administration of evening agomelatine medication has a crucial importance in terms of efficacy, furthermore confirm the results of previous international clinical trials that the antidepressant agomelatine exerts the same strength of antidepressant effect as the clinically proven escitalopram.

Association between depression and the Gln460Arg polymorphism of P2RX7 gene: a dimensional approach.

The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a novel candidate gene for major depressive disorder (MDD) and bipolar disorder (BPD). The proposed risk allele (G-allele) of the rs2230912 polymorphism results in an amino acid change at the 460th position, marking this genetic variation a possibly functional one. Here we present a case-control analysis of 171 patients diagnosed with MDD or BPD and 178 controls, as well as a dimensional approach using the Hospital Anxiety and Depression Scale (HADS) for studying the Gln460Arg polymorphism of the P2RX7 gene as a genetic risk factor in depression. While case-control analysis did not show significant difference between the groups, a significant association was found between the P2RX7 polymorphism and the HADS scales in the clinical group (MANOVA P = 0.001). Both anxiety and depression scores increased as the number of G-allele increased in the genotype groups (ANOVA for HADS-anxiety: P = 0.01, HADS-depression: P < 0.001). A significant interaction of clinical status and the P2RX7 polymorphism was also found for the depression scale (MANOVA P = 0.025, subsequent ANOVA for anxiety: P = 0.252; depression: P = 0.002). Whereas patients with G-allele-present genotypes showed more elevated depression scores, level of depression in the control group was not affected by the P2RX7 genotype. In conclusion, case-control analysis did not reveal significant results, but using a symptom severity scale we could support the association between depressive disorder and the G-allele of the Gln460Arg polymorphism in the P2RX7 gene.

[Validation of a new mood questionnaire on healthy sample]. / Egy új hangulati kérdoív validálása egészséges mintán.

Depression is a frequent, wide spectrum disease causing substantial suffering. Quantitative tools for measuring depression are rather important both at the clinical and non-clinical state. BDI (Beck Depression Inventory) the HADS (Hospital Anxiety and Depression Scale) and the BHS (Beck Hopelessness Scale) are used both in clinical practice and research. Primary aim of these questionnaires is the diagnosis of clinical depression, however, screening for less severe stages of depression, and realization of predisposition to depression is also important. Based on results from recent twin-studies genetic factors of depression are significant. Moreover, discovering genetic risk factors of depression is a challenging task of psychogenetic association studies. Creating new endophenotypes, those units of our phenotypic makeup which can be objectively measured and are linked to certain genetic components, is an important step in completion of this challenge. The primary goal of the present study was to characterize predisposition to depression with endophenotypes suitable for genetic association analysis. To achieve this goal 170 participants filled out the BDI and HADS questionnaires in the first stage of the study (99 were diagnosed with clinical depression, and 71 were healthy adults). Psychometric properties of these questionnaires were assessed, reliability of the Hungarian version of both scales proved to be satisfactory. Using items from these tools we derived a common factor structure in order to create a new, short measure (the DS1K) of the depression construct ready to be used as endophenotype in psychogenetic association studies. Usability of the DS1K was assessed based on data from 144 healthy adults. The measure proved to be highly reliable (Cronbach-alpha = 0.88) and valid (correlation with the BDI and HADS scales were high and significant).

Association of the STin2 polymorphism of the serotonin transporter gene with a neurocognitive endophenotype in major depressive disorder.

BACKGROUND: The aim of our study was to investigate the association of STin2 polymorphism and cognitive dysfunction in major depression. METHODS: 71 patients with major depression and 99 controls were genotyped for STin2. All depressive subjects and 30 controls also completed tests measuring neurocognitive performance. RESULTS: We found a significantly higher frequency of the STin2.10/Stin2.10 homozygous genotype in the depressed group compared to controls. In the depressed group subjects with at least one copy of the 10-repeat allele showed decreased interference threshold in Stroop III compared to patients without the 10-repeat allele. Average performance of the depressed group without the 12-repeat allele was significantly weaker in the Rey Auditory Verbal Learning Test working memory and recall tasks compared to patients having at least one copy of the 12-repeat allele. CONCLUSION: Our results suggest that the presence of STin2.10 and absence of STin2.12 allele may be related to a possible genetic endophenotype for characteristic cognitive dysfunctions detected in MDD.

[Association of neurocognitive endophenotype and STin2 polymorphism in major depressive disorder]. / Neurokognitív endofenotípus és STin2 polimorfizmus asszociáció vizsgálata major depresszióban.

Two well known polymorphic regions of the serotonin transporter gene (SLC6A4) are the 5HT-TLPR which consists of a 44-bp insertion or deletion in the promoter region and the STin2 consisting of variable number of tandem repeats in the second intron. Several studies focused on the association of the 5HTTLPR and behavioral or clinical factors of depression; on the other hand, the relation of the STin2 to major depressive disorder (MDD) is less widely investigated. We carried out a case-control study of 71 MDD patients and 99 healthy control subjects comparing frequencies of the STin2 allele- and genotype variants in the two populations. We found a significantly higher frequency of the STin2 10/10 homozygous genotype in the MDD patients' group compared to controls (chi2 = 6,01, df = 2, p < 0.05). To further explore possible endophenotypes of neurocognitive functioning in the background of this disorder we measured performance of 71 cases and 30 matched controls using several tests of neurocognitive functioning. Our results indicated cognitive dysfunctions of the MDD patients in all tests as compared to control individuals. The clinical subgroup with at least one copy of the 10-repeat allele showed a decreased interference threshold in Stroop III as compared to patients without the 10-repeat allele. Average performance of the clinical subgroup without the 12-repat allele proved to be significantly weaker in the working memory and recall tasks (RAVLT) compared to patients having at least one copy of the 12-repeat allele. After further confirmation our results suggest that the presence of STin2.10 and absence of STin2.12 allele may be defined as a possible genetic endophenotype for cognitive dysfunctions detected in MDD.

Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1.

Activated protein C (APC) exerts endothelial protein C receptor (EPCR)-dependent neuroprotective effects in a brain focal ischemia model and direct cellular effects on human umbilical vein endothelial cells (HUVECs) via protease-activated receptor-1 (PAR-1). Because PAR receptors are expressed in brain endothelium and mediate intracellular calcium concentration ([Ca2+]i) signaling, we hypothesized that APC may regulate intracellular [Ca2+] flux in human brain endothelial cells (BECs) via EPCR and PAR-1. Primary cortical BECs derived from human autopsies (early passage) and HUVECs were used for [Ca2+]i imaging fluorometry. Cells were exposed for 1 minute to APC, protein C zymogen, or mutant Ser360Ala-APC, and [Ca2+]i was monitored in the presence or absence of antibodies against PAR-1, PAR-2, PAR-3, or EPCR. APC, but not protein C zymogen or the active site mutant Ser360Ala-APC, induced dose-dependent [Ca2+]i release in human BECs (Delta[Ca2+]i max = 278.3 +/- 19.5 nM; EC50 for APC = 0.23 +/- 0.02 nM, n = 70 measurements). APC-induced [Ca2+]i signaling was abolished by a cleavage site blocking anti-PAR-1 antibody, whereas anti-PAR-2 and -PAR-3 antibodies were without effect. Antibody RCR252 that ablates APC binding to EPCR blocked APC-mediated [Ca2+]i signaling, whereas anti-EPCR antibody RCR92 that does not block APC binding did not abolish the APC-induced [Ca2+]i response. Experiments using HUVECs confirmed the findings for BECs. Thapsigargin inhibited the APC-induced [Ca2+]i signal, implicating the endoplasmic reticulum as a major source for the APC-induced [Ca2+]i release. These data suggest that APC regulates [Ca2+]i in human brain endothelium and in HUVECs by binding to EPCR and signaling via PAR-1.

Protease-activated receptor-2 (PAR-2) in brain microvascular endothelium and its regulation by plasmin and elastase.

Protease-activated receptors (PARs) mediate cell activation after proteolytic cleavage of their extracellular amino terminus. We have reported earlier that primary cultures of rat brain capillary endothelial (RBCE) cells express at least two receptors for thrombin: PAR-1 and PAR-3. In the present study we show that PAR-2 activation by trypsin or by the PAR-2 agonist peptide (SLIGRL) evokes [Ca(2+) ](i) signal in RBCE cells. Taking advantage of RBCE cells expressing PAR-1 and PAR-2, we show that trypsin activates both receptors. The relative agonist activity of trypsin and thrombin on PARs of RBCE cells compared with that of SLIGRL were 112% and 48%, respectively, whereas the potency of trypsin was 10(5) -fold higher than that of SLIGRL. Because under pathological conditions other proteases such as plasmin or leukocyte elastase may reach the cells of the blood-brain barrier, we investigated the effect of these proteases on RBCE cells. Elastase evoked a small increase in [Ca(2+) ](i) but preincubation of cells with elastase dose-dependently reduced the trypsin-induced [Ca(2+) ](i) signal. Plasmin had a 30% inhibitory effect on the trypsin-induced response, and reduced the SLIGRL signal by 20%. It is concluded that PAR-2 is functional in brain capillary endothelium, and that the main fibrinolytic proteases, plasmin and elastase, may regulate PAR-2 signalling under pathological conditions.