[Association between mood characteristics and polymorphisms of glial cell line-derived neurotrophic factor (GNDF) in patients with depression]. / A hangulati dimenziók és a glia-eredetü növekedési faktort kódoló gén polimorfizmusainak összefüggése depresszióval diagnosztizált mintán.

Glial cell line-derived neurotrophic factor (GNDF) plays an important role in the development and synaptic plasticity of dopaminergic neurons, thus it could be an important therapeutic factor in Parkinson's disease. Results from candidate gene studies of GDNF in psychiatric disorders are contradictory. Moreover, the possible association between GDNF polymorphisms and major- or bipolar depression has not been studied to date. Recently, our research group has published an association between two GDNF polymorphisms (rs3812047, rs3096140) and the individual variability of anxiety measured by the Hospital Anxiety and Depression Scale (HADS) on a non-clinical sample. In the present study we further analyzed this association on a sample with major- and bipolar depression: we used data from 183 MDD, 116 BP, and 1172 control subjects and tested effect of GDNF rs3812047 and rs3096140 polymorphisms on mood disorders. The case control design did not show significant differences in the genotype distribution of BP or MDD versus control patients. However, in the bipolar group subjects with rs3812047 A allele showed a significantly higher anxiety and depression mean score then subjects with G allele (p=0.043). This result supports our previous findings demonstrated on a non-clinical sample. Interestingly we found an opposite effect of the rs3812047 using data from MDD patients: subjects with the G allele had higher depression scores (p=0.012). An interaction effect of patient subgroups and genetic variants of the rs3812047 was observed for both HADS subscales (anxiety: p=0.029; depression: 0.004). In summary, we confirmed the previously published association between the rs3812047 A allele and mood characteristics on the bipolar sample, and an effect in the opposite direction was detected in the patient group with major depression.

Hungarian validation of the Buss-Perry Aggression Questionnaire-Is the short form more adequate?

OBJECTIVE: We aim to provide a publicly available Hungarian version of the BPAQ; compare the BPAQ factors to other personality traits; and compare both the original BPAQ factor structure provided by Buss and Perry (J. Pers. Soc. Psychol., 63, 1992, 452), the revised BPAQ-SF factor structure by Bryant and Smith (J. Res. Pers., 35, 2001, 138), and the BAQ by Webster et al. (Aggress. Behav., 40, 2014, 120). METHODS: The validation of the Hungarian version of the BPAQ was carried out on a Hungarian university sample (N = 841). There were three main focuses of data analysis: descriptive statistics, correlations, and confirmatory factor analyses. RESULTS: CFA-related statistics showed an adequate fit for the BPAQ 4 factors; however, contrary to prior validations of BPAQ, we were not able to clearly define the verbal aggression factor. We found that the shorter form of the BPAQ has a better model fit on our sample than the original form, while the model fit of the BAQ was in-between these. BPAQ scales showed low to moderate relationship with the Barratt Impulsivity Scale and Hospital Anxiety and Depression Scale. CONCLUSION: Both the BPAQ and the BPAQ-SF, also the BAQ provide acceptable model fitting on a Hungarian sample of university students. While most of BPAQ items provided adequate loadings on their hypothesized factors, two items (21 and 27) did not. We argue this is the result of conceptual inaccuracy of the original items.

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.

Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms.

INTRODUCTION: The activation of the ATP-gated P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) produces microglial activation, a process which has been demonstrated in depression, bipolar disorder, and schizophrenia. Emerging data over the last years highlighted the importance of P2X7 cation channel as a potential drug target for these central nervous system disorders. The Gln460Arg (rs2230912) polymorphism of the P2RX7 gene has been widely studied in mood disorders, however the results are still controversial. Therefore, we aimed to investigate the C-terminal region of this gene in major depressive and bipolar disorders (MDD and BD) by studying possibly functional, non-synonymous polymorphisms within a 7 kb long region around the Gln460Arg, including Ala348Thr (rs1718119), Thr357Ser (rs2230911), and Glu496Ala (rs3751143) variants. Since Gln460Arg is located at the 3' end of the P2RX7 gene, we included additional, potentially functional single nucleotide polymorphisms (SNPs) from the 3' untranslated region (UTR), which can be in linkage with Gln460Arg. Based on in silico search, we chose two SNPs in putative microRNA target sites which are located in consecutive positions: rs1653625 and rs1718106. METHODS: P2RX7 SNPs from the C-terminal region were selected based on previous functional assays, 3' UTR variants were chosen using PolymiRTS and Patrocles databases. The genotyping of the non-synonymous SNPs was carried out by pre-designed TaqMan® kits, while the 3' UTR variants were analyzed by PCR-RFLP method. Case-control analyses were carried out between 315 inpatients with acute major depressive episode (195 MDD, 120 BD) and 406 healthy control subjects. The two subscales of the Hospital Anxiety and Depression Scale (HADS) self-report questionnaire were used for quantitative analyses, including an additional, "at-risk" population of 218 patients with diabetes mellitus. The in vitro reporter gene assays were carried out on HEK and SK-N-FI cells transiently transfected with pMIR vector constructs containing the P2RX7 3' UTR downstream of the luciferase gene. RESULTS: Haplotype analysis indicated a relatively high linkage between the analyzed P2RX7 SNPs. Our case-control study did not yield any association between P2RX7 gene variants and depression. However, dimensional analyses showed significant associations of the HADS depression severity scores with Gln460Arg (rs2230912) and Ala348Thr (rs1718119) in the depressed and diabetic patient groups. In the in vitro experiments, the P2RX7 3' UTR constructs with the lowest predicted binding efficiency to their miRNAs showed the highest expression of the gene. The combination of the depression-associated P2RX7 C-terminal and 3' UTR SNPs contributed to the highest depression severity score in the haplotype analysis. CONCLUSION: Based on our findings, we propose that a P2RX7 haplotype combination of the Gln460Arg and neighboring SNPs contribute to the observed genetic association with depressive symptoms.

[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).

Associations between depression severity and purinergic receptor P2RX7 gene polymorphisms.

BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BPD) have significant genetic predisposition. The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a susceptibility gene for both MDD and BPD. In the current study the genetic effects of rs2230912 (Gln460Arg) and rs1653625 (located in the 3' untranslated region of the P2RX7 gene) were explored in mood disorders. METHODS: Genotype frequencies were established in 315 patients (195 with MDD and 120 with BPD diagnosis) and in 373 controls. Depression severity was assessed by the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) and by the self-report Hospital Anxiety and Depression Scale (HADS). RESULTS: In the case-control analysis we did not find any significant differences between genotype frequencies of either BPD or MDD cases and controls. However, BPD patients carrying at least one rs2230912G-allele scored higher on both MADRS and HADS-depression scale (nominal p-value was 0.028 and 0.003, respectively). The rs1653625AA genotype was also associated with higher depression scores in the BPD group (nominal p-value of MADRS: 0.019, HADS-depression: 0.017). After correction for multiple testing, the association between rs2230912 and HADS-depression score remained significant in the BPD group (p<0.006); this genetic effect explained 9% of the variance (partial η(2)=0.09). In the MDD group we did not find any significant genetic effect. LIMITATIONS: The relatively small number of BPD patients warrants for a replication study. CONCLUSIONS: Our genetic association study supports the association between P2RX7 gene and severity of depressive symptoms in BPD patients.

Peripheral vascular endothelial growth factor level is associated with antidepressant treatment response: results of a preliminary study.

BACKGROUND: Recent investigations have revealed multiple actions of vascular endothelial growth factor (VEGF) in the nervous system. The role of VEGF in the molecular background of mood disorders has also been proposed. In this study we were interested in investigating a possible association between VEGF levels and treatment response in patients with a current episode of major depression (MDE). METHODS: 34 patients with MDE were enrolled in our study. Depressive symptoms were monitored by the Montgomery-Åsberg Depression Rating Scale at baseline (V(1)) and after a 4-week treatment period (V(2)). Patients with less than a 50% improvement in MADRS total scores during this period were regarded as non-responders. RESULTS: Plasma VEGF levels did not change during the treatment period in either the total sample or in the responder and non-responder subsamples. There was a strong trend for higher baseline VEGF levels in the non-responder group than in the responder group (p=0.055) and this difference-as a weak trend-was still detectable at the end of the treatment period (p=0.097). Regression analysis revealed that the baseline VEGF level was a significant predictor for the endpoint MADRS score (p=0.02). LIMITATIONS: Sample size was relatively small; sample consists of both patients with MDD and bipolar disorder. CONCLUSIONS: Our preliminary results raise the possibility that baseline levels of peripheral VEGF may predict treatment response in patients with mood disorders. Considering the limitations of our study, further investigations should resolve whether VEGF is a useful biomarker for treatment response in depression in clinical practice.

Investigation of circulating endothelial progenitor cells and angiogenic and inflammatory cytokines during recovery from an episode of major depression.

BACKGROUND: Epidemiological studies strongly suggest a bidirectional positive relationship between mood and cardiovascular disorders (CVD). Reduced numbers of circulating endothelial progenitor cells (cEPCs) are associated with elevated risks of CVD. Previously we demonstrated that patients with a current episode of major depression (MDE) have a decreased number of cEPCs. The role of vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF) has been demonstrated in the etiopathogenesis of depression. In addition these cytokines are also involved in regulation of the vascular system. This suggests that VEGF and/or TNF may also mediate the elevated risk of CVD associated with mood disorders. METHODS: In the current investigation, which has a self-controlled study design, we examined changes in VEGF and TNF levels and--for the first time--changes in cEPC number during recovery from MDE. RESULTS: Twenty-four patients with MDE were enrolled. The severity of their depressive symptoms improved significantly during the one-month treatment period (~50% decrease in MADRS score; P≤0.001). We did not find significant differences between baseline and end-point levels of VEGF, TNF and the number of cEPCs. CONCLUSION: Our negative result for alteration in the number of cEPCs in the course of recovery from MDE raises several questions. Before discarding the number of cEPCs as a possible marker of depression--and/or elevated CV risk associated with it--our results would require confirmation in larger samples. Our results for TNF and VEGF do not contradict the findings of prior studies, since these were controversial.

Association between hypnotizability and the catechol-O-methyltransferase (COMT) polymorphism.

Previous studies implicate involvement of dopaminergic systems in hypnotizability and report association with the COMT Val(158)Met single nucleotide polymorphism (SNP, rs4680) demonstrating the Val/Met heterozygotes as the most hypnotizable group using the Stanford Hypnotic Susceptibility Scale. This study replicates that association using an independent sample of 127 healthy Hungarian young adults and the Waterloo-Stanford Group C Scale of Hypnotic Susceptibility. Significant association (p = .016) was found between the COMT genotypes and hypnotizability, with a clear additive effect of the Val allele: Hypnotizability scores were highest in Val/Val (5.9), intermediate in Val/Met (4.7), and lowest in Met/Met (4.1). Differences between these results and those of previous studies support recent findings suggesting an inverted-U-shaped relation between dopamine level in the prefrontal cortex and cognitive functioning. The present study replicates association of COMT Val(158)Met SNP and hypnotizability and stresses the importance of mediating factors, such as group vs. individual inductions.