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Abstract The heterogeneity and complexity of symptom presentation, comorbidities and genetic factors pose challenges to the identification of biological mechanisms underlying complex diseases. Current approaches used to identify biological subtypes of major depressive disorder (MDD) mainly focus on clinical characteristics that cannot be linked to specific biological models. Here, we examined multimorbidities to identify MDD subtypes with distinct genetic and non-genetic factors. We leveraged dynamic Bayesian network approaches to determine a minimal set of multimorbidities relevant to MDD and identified seven clusters of disease-burden trajectories throughout the lifespan among 1.2 million participants from cohorts in the UK, Finland, and Spain. The clusters had clear protective- and risk-factor profiles as well as age-specific clinical courses mainly driven by inflammatory processes, and a comprehensive map of heritability and genetic correlations among these clusters was revealed. Our results can guide the development of personalized treatments for MDD based on the unique genetic, clinical and non-genetic risk-factor profiles of patients.

Abstract The present study aimed to investigate whether the strength of mental health competencies and the severity of mental disorder symptoms, and their interaction, differ in the strength of their associations with several dimensions of well-being in Hungarian adult psychiatric and non-clinical samples. All respondent in the psychiatric sample (129 patients (44 male, 85 female)) and in the non-clinical community sample (253 adults (43 male, 210 female)) completed the Mental Health Test, six measures of well-being and mental health, and the Symptom Checklist-90-Revised. Including both mental health competencies and mental disorder symptoms in a regression model in both samples can predict patients’ well-being even more accurately. Mental health competencies were positively related; mental disorder symptoms were negatively related to subjective well-being. In all models and in both samples, mental health competencies were found to be stronger determinants of well-being than mental disorder symptoms. The interaction of mental health competencies and mental disorder symptoms is no more predictive of well-being in either psychiatric or non-clinical samples than when the effects of each are considered separately. The assessment of mental health competencies has an important predictive value for well-being in the presence of psychopathological symptoms and/or mental disorders.

The increasing relevance of PTSD issues is associated with the escalation of military conflicts worldwide. Complex biological mechanisms also play a significant role in the pathogenesis of PTSD, including those changes observed in the hippocampus and other brain structures. Aim– to identify the most significant genetic markers predisposing the risk of PTSD manifestation, which could contribute to the development of targeted interventions focusing on the preventive measures and treatment strategies of this disorder. A literature search was conducted in the PubMed database using keywords related to the genetics of PTSD, with a publication time restriction from 2018 to 2023. Out of 623 papers, 20 articles met the inclusion criteria, describing molecular-genetic and statistical data, and the sample size of at least 60 patients with a verified PTSD diagnosis, were reviewed and analyzed in detail. The studies revealed significant associations between PTSD occurrence and single nucleotide variants (SNVs) in the FKBP5 and CRHR1 genes. Particular attention was paid to the interactions between SNVs of different genes and their association with the severity of PTSD clinical manifestations. Conclusions.Genetic markers, in particular, SNVs in the FKBP5 (rs9470080) and CRHR1 (rs1724402) genes, may play a key role as the risk factors for biological predisposition and the PTSD development. These findings would underlie the targeted interventions integrated into PTSD-related prevention measures and treatment strategies. However, further multicenter and consortium studies with unified design are required to confirm the significance of the identified associations and to specify the epigenetic aspects contributing to the PTSD manifestation and development.

Abstract Affective temperaments have been shown to robustly affect infertility treatment success. However, identification of possible mediating factors through which they exert their influence is still lacking. A growing number of results suggest that adherence to recommended treatments may be such a mediator, on the one hand, because affective temperaments are known to influence adherence and, on the other hand, because non-adherence negatively influences the treatment outcome. Recommended treatment of infertility involves, beyond medications, dietary and lifestyle changes. The aim of this retrospective cohort study was to evaluate whether adherence to physician-prescribed diet and physical activity recommendations mediates the effect of affective temperaments on infertility treatment outcomes. Among 308 women who underwent infertility treatment in an Assisted Reproduction Center, affective temperaments, adherence to diet, adherence to physical exercise, and infertility treatment success (clinical pregnancy) were assessed besides detailed medical history and demographic parameters. Associations between affective temperaments, adherence to diet and recommended physical activity, and assisted reproduction outcomes were analyzed using generalized linear models and causal mediation analysis. Adherence to physical activity didn’t have an effect, but diet adherence increased the odds of infertility treatment success by 130% suggesting its role as a potential mediator. Based on causal mediation analysis, higher depressive and anxious temperament scores were directly associated with 63% and 45% lower odds of achieving clinical pregnancy, respectively, with effects not mediated by diet adherence. Higher irritable temperament scores indirectly decreased the odds of achieving clinical pregnancy by 14%, mediated by diet adherence; while higher cyclothymic temperament scores decreased the odds of achieving clinical pregnancy both directly by 51% and indirectly, mediated by diet adherence by 11%. Our results suggest that diet adherence mediates the mechanism by which irritable and cyclothymic affective temperaments influence IVF treatment success. Since adherence is a modifiable risk factor of infertility treatment success, screening for affective temperaments may help to identify potentially high-risk non-adherent patient groups and offer patient-tailored treatment, which may help increase the chances of a successful pregnancy and live birth in women undergoing IVF treatment.

Abstract Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.

Abstract To assist psychiatrists and clinical psychologists to assess their patients’ psychological immune competence-based capacities and resources, depending on the mental health disorder diagnosis and the severity of the symptoms, the present study examined the psychometric properties of the Mental Health Test in a psychiatric sample. The research was carried out in four Hungarian healthcare facilities using a cross-sectional design. A total of 331 patients (140 male, 188 female, and 3 who preferred not to disclose their gender) completed the Mental Health Test, six well-being and mental health measures, and the Symptom Checklist-90. Psychiatrists and clinical psychologists reported the mental disorder status of each participant. Confirmatory factor analysis showed a good fit of the five-factor model to the data for the clinical version of the Mental Health Test (CFI = 0.972, RMSEA = 0.034). High internal consistency coefficients (α: 0.70–0.84; ω: 0.71–0.85) and excellent external and content validity were reported. The test is not sensitive to sociodemographic indicators but is sensitive to the correlates of well-being and to the symptoms of different types of mental disorders. Our preliminary findings suggest that the Mental Health Test is a suitable measure for assessing mental health capacities and resources in psychiatric samples.

Abstract Infertility has a multifactorial background, where, besides somatic factors, psychological contributors also play a role in development and outcome. While affective temperaments have been associated with development, course, and outcome as well as treatment success in various somatic conditions, their association with infertility and its treatment has not been investigated so far. The purpose of our retrospective cohort study was to evaluate the influence of affective temperaments on fertility treatment outcomes. Among 578 women who underwent infertility treatment in an Assisted Reproduction Centre in Budapest, Hungary, treatment success, detailed medical history, and demographic parameters were recorded, and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A) was administered. Possible predictors of assisted reproduction outcome were analyzed using multivariate logistic regression models, followed by a receiver operating curve (ROC) analysis in order to define ideal affective temperament cut-off values for clinical applicability. Aside from age, BMI, and previous miscarriage, cyclothymic scores > 4 (OR = 0.51 CI 0.35–0.74, p 9 (OR = 0.59 CI 0.4–0.87, p = 0.009) and anxious scores > 9 (OR = 0.45 CI 0.31–0.66, p

IntroductionThe aim of the study was to search rates of depression and mental health in university students, during the COVID-19 pandemic.Materials and methodsThis is an observational cross-sectional study. A protocol gathering sociodemographic variables as well as depression, anxiety and suicidality and conspiracism was assembled, and data were collected anonymously and online from April 2020 through March 2021. The sample included 12,488 subjects from 11 countries, of whom 9,026 were females (72.2%; aged 21.11 ± 2.53), 3,329 males (26.65%; aged 21.61 ± 2.81) and 133 “non-binary gender” (1.06%; aged 21.02 ± 2.98). The analysis included chi-square tests, correlation analysis, ANCOVA, multiple forward stepwise linear regression analysis and Relative Risk ratios.ResultsDysphoria was present in 15.66% and probable depression in 25.81% of the total study sample. More than half reported increase in anxiety and depression and 6.34% in suicidality, while lifestyle changes were significant. The model developed explained 18.4% of the development of depression. Believing in conspiracy theories manifested a complex effect. Close to 25% was believing that the vaccines include a chip and almost 40% suggested that facemask wearing could be a method of socio-political control. Conspiracism was related to current depression but not to history of mental disorders.DiscussionThe current study reports that students are at high risk for depression during the COVID-19 pandemic and identified specific risk factors. It also suggested a role of believing in conspiracy theories. Further research is important, as it is targeted intervention in students' groups that are vulnerable both concerning mental health and conspiracism.

Abstract Suicides are often related to depression. General medical practices (GMPs) should play a role in screening depression. We aimed to test the screening algorithm of Rihmer and Torzsa for depression and suicide and determine the prevalence and number of patients in the nationwide representative Hungarostudy 2002 population, and to estimate the corresponding extra health care need in an average GMP and in the Hungarian population in addition to patients who are already cared for by specialized care. The short version of the Beck Hopelessness Scale (BHS) and the Hungarian version of the short form of the Beck Depression Inventory (BDI-9) were used to screen for suicide risk and depression. The prevalence of suicidal thoughts and depression was determined and findings were extrapolated to an average GMP of 1,600 adults and to the population over 25 years of age. This screening would generate a considerable extra psychiatric care to organize and implement in an average GMP and throughout the country. Our findings show that with easily administered screening instruments a significant number of patients likely to have depression can be identified at the primary care level, arguing for the establishment of the extra psychiatric care capacity in Hungary.

Abstract Emotional stress is a leading risk factor in the development of neuropsychiatric disorders possibly via immune activation. P2X7 receptors promote neuroinflammation, and research suggests a relationship between chromosome region 12q2431, in which the P2X7R gene is located, and development of mood disorders, however, few studies concentrate on its association with anxiety. Our aim was to investigate the effects of P2RX7 variation in interaction with early childhood traumas and recent stressors on anxiety. 1752 participants completed questionnaires assessing childhood adversities and recent negative life events, provided data on anxiety using the Brief Symptom Inventory, and were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into linear regression models followed by a linkage disequilibrium-based clumping procedure to identify clumps of SNPs with a significant main or interaction effect. We identified a significant clump with top SNP rs67881993 and containing a set of 29SNPs that are in high LD, which significantly interacted with early childhood traumas but not with recent stress conveying a protective effect against increased anxiety in those exposed to early adversities. Our study demonstrated that P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms, supporting previous scarce results and demonstrating its role in moderating the effects of stress.

Abstract Manipulation of intake of serotonin precursor tryptophan has been exploited to rapidly induce and alleviate depression symptoms. While studies show that this latter effect is dependent on genetic vulnerability to depression, the effect of habitual tryptophan intake in the context of predisposing genetic factors has not been explored. Our aim was to investigate the effect of habitual tryptophan intake on mood symptoms and to determine the effect of risk variants on depression in those with high and low tryptophan intake in the whole genome and specifically in serotonin and kynurenine pathways. 63,277 individuals in the UK Biobank with data on depressive symptoms and tryptophan intake were included. We compared two subpopulations defined by their habitual diet of a low versus a high ratio of tryptophan to other large amino acids (TLR). A modest protective effect of high dietary TLR against depression was found. NPBWR1 among serotonin genes and POLI in kynurenine pathway genes were significantly associated with depression in the low but not in the high TLR group. Pathway-level analyses identified significant associations for both serotonin and kynurenine pathways only in the low TLR group. In addition, significant association was found in the low TLR group between depressive symptoms and biological process related to adult neurogenesis. Our findings demonstrate a markedly distinct genetic risk profile for depression in groups with low and high dietary TLR, with association with serotonin and kynurenine pathway variants only in case of habitual food intake leading to low TLR. Our results confirm the relevance of the serotonin hypothesis in understanding the neurobiological background of depression and highlight the importance of understanding its differential role in the context of environmental variables such as complexity of diet in influencing mental health, pointing towards emerging possibilities of personalised prevention and intervention in mood disorders in those who are genetically vulnerable.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

Abstract Background Predominant affective temperament may affect adherence to prescribed pharmacotherapeutic interventions, warranting systematic review and meta-analysis. Methods The Scopus, Web of Science, PubMed, and OVID MedLine databases were inquired since inception up to 31st of March 2022 for records of any study design documenting quantitative evidence about affective temperaments as measured by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego (TEMPS-A) questionnaire and treatment adherence measured by the means of major rating scales on the matter. People with low vs. high levels of treatment adherence, matched for otherwise clinically relevant variables, were deemed as cases and controls, respectively, using standardized mean differences (SMDs) in pertinent scores under random-effects meta-analysis. Results Nine studies encompassing 1138 subjects pointed towards significantly higher cyclothymic (SMD = −0.872; CI: [−1.51 to −0.24]; p = 0.007), irritable (SMD = −0.773; CI: [−1.17 to −0.37]; p

BackgroundData from primary care regarding the prevalence of symptoms of depression and anxiety, and their effect on glycemic control among people with diabetes is lacking in Hungary. The recently introduced Patient Health Record (PHR) requires family doctors to screen for depressive symptoms.ObjectivesWe aimed to investigate the prevalence of depressive and anxiety symptoms among patients with type 2 diabetes in the general practice, and the relationship between these affective disorders and glycated hemoglobin (HbA1c) level.MethodsWe included 338 consecutive patients with type 2 diabetes from six primary care practices in this cross-sectional study. A self-administered questionnaire (patient history, anthropometric, socioeconomic, laboratory parameters), the Beck Depression Inventory (BDI) and the Hamilton Anxiety Scale (HAM-A) were used.ResultsThe mean age of the sample was 64.0 ± 11.5 (years ± SD), 61% of participants were female. The prevalence of depressive symptoms was 21%, mainly moderate/severe symptoms (13%). Anxiety symptoms were more common (35%). We found significant univariate association between the depressive symptoms and HbA1c (p = 0.001), suicide attempt (p < 0.001), anxiety (p < 0.001), micro- and macrovascular complication (p = 0.028 and p < 0.001), education (p = 0.001) and place of residence (p = 0.002). In multivariate analysis, however, only BDI score had significant (p = 0.03191) association with glycemic control.ConclusionAmong primary care patients with type 2 diabetes, the prevalence of depressive symptoms was less frequent than anxiety symptoms. More severe depressive symptoms were associated with worse glycemic control.

The fight against suicide is highly challenging as it may be one of the most complex and, at the same time, most threatening among all psychiatric phenomena. In spite of its huge impact, and despite advances in neurobiology research, understanding and predicting suicide remains a major challenge for both researchers and clinicians. To be able to identify those patients who are likely to engage in suicidal behaviors and identify suicide risk in a reliable and timely manner, we need more specific, novel biological and genetic markers/indicators to develop better screening and diagnostic methods, and in the next step to utilize these molecules as intervention targets. One such potential novel approach is offered by our increasing understanding of the involvement of neuroinflammation based on multiple observations of increased proinflammatory states underlying various psychiatric disorders, including suicidal behavior. The present paper overviews our existing understanding of the association between suicide and inflammation, including peripheral and central biomarkers, genetic and genomic markers, and our current knowledge of intervention in suicide risk using treatments influencing inflammation; also overviewing the next steps to be taken and obstacles to be overcome before we can utilize cytokines in the treatment of suicidal behavior.

Abstract Although recently a large-sample GWASs identified significant loci in the background of depression, the heterogeneity of the depressive phenotype and the lack of accurate phenotyping hinders applicability of findings. We carried out a pilot GWAS with in-depth phenotyping of affective temperaments, considered as subclinical manifestations and high-risk states for affective disorders, in a general population sample of European origin. Affective temperaments were measured by TEMPS-A. SNP-level association was assessed by linear regression models, assuming an additive genetic effect, using PLINK1.9. Gender, age, the first ten principal components (PCs) and the other four temperaments were included in the regression models as covariates. SNP-level relevances (p-values) were aggregated to gene level using the PEGASUS method1. In SNP-based tests, a Bonferroni-corrected significance threshold of p ≤ 5.0 × 10−8 and a suggestive significance threshold of p ≤ 1.0 × 10−5, whereas in gene-based tests a Bonferroni-corrected significance of 2.0 × 10−6 and a suggestive significance of p ≤ 4.0 × 10−4 was established. To explore known functional effects of the most significant SNPs, FUMA v1.3.5 was used. We identified 1 significant and 21 suggestively significant SNPs in ADGRB3, expressed in the brain, for anxious temperament. Several other brain-relevant SNPs and genes emerged at suggestive significance for the other temperaments. Functional analyses reflecting effect on gene expression and participation in chromatin interactions also pointed to several genes expressed in the brain with potentially relevant phenotypes regulated by our top SNPs. Our findings need to be tested in larger GWA studies and candidate gene analyses in well-phenotyped samples in relation to affective disorders and related phenotypes.

Abstract Repetitive transcranial magnetic stimulation (rTMS) is an effective and well tolerable biological intervention in major depressive disorder (MDD) contributing to rapid symptom improvement. Molecular mechanisms underpinning the therapeutic effects of rTMS have still not been clarified. Recently published animal data implicated relevant associations with changes in endocannabinoid (eCB) brain levels during rTMS treatment, human studies, however, have not been published. In our study we assessed the detailed phenotypic spectrum of MDD and serum 2-arachidnoylglycerol (2-AG) and anandamide (AEA) levels in 18 patients with treatment-resistant depression before, immediately following, and two weeks after completion of a 10-day rTMS treatment. We found significant associations between serum 2-AG level changes from pretreatment to 2 weeks after treatment and symptom reduction. The greater the increase of 2-AG levels, the greater the improvement of depressive (p = 0.031), anxious (p = 0.007) and anhedonia symptoms (p = 0.047). Here we report for the first time a significant association of human circulating eCB and antidepressant effect of rTMS. Our data may indicate that direct stimulation of targeted brain areas can rapidly alleviate depressive complaints via activation of the eCB system.

Background: Understanding and predicting suicide remains a challenge, and a recent paradigm shift regarding the complex relationship between the immune system and the brain brought attention to the involvement of inflammation in neuropsychiatric conditions including suicide. Among cytokines, IL-6 has been most frequently implicated in suicide, yet only a few candidate gene studies and without considering the effect of stress investigated the role of IL6 in suicidal behaviour. Our study aimed to investigate the association of IL6 variation with a linkage disequilibrium-based clumping method in interaction with childhood adversities and recent stress on manifestations along the suicide spectrum.Methods: One thousand seven hundred and sixty-two participants provided information on previous suicide attempts, current suicidal ideation, thoughts of death, and hopelessness, and were genotyped for 186 variants in IL6. Early childhood adversities were recorded with an instrument adapted from the Childhood Trauma Questionnaire, recent life events were registered using the List of Threatening Life Events. Following a 3-step quality control, logistic and linear regression models were run to explore the effect of genotype and gene-environment interactions on suicide phenotypes. All regression models were followed by a clumping process based on empirical estimates of linkage disequilibrium between clumps of intercorrelated SNPs. Interaction effects of distinct types of recent life events were also analysed.Results: No clumps with significant main effects emerged, but we identified several clumps significantly interacting with childhood adversities on lifetime suicide attempts, current suicidal ideation, and current thoughts of death. We also identified clumps significantly interacting with recent negative life events on current suicidal ideation. We reported no clumps with significant effect on hopelessness either as a main effect or in interaction with childhood adversities or recent stress.Conclusion: We identified variant clumps in IL6 influencing suicidal behaviour, but only in interaction with childhood or recent adversities. Our results may bring us a step further in understanding the role of neuroinflammation and specifically of IL-6 in suicide, towards identifying novel biological markers of suicidal behaviour especially in those exposed to stressful experiences, and to fostering the adaptation of a new paradigm and identifying novel approaches and targets in the treatment of suicidal behaviour.

The role of circadian dysregulation is increasingly acknowledged in the background of depressive symptoms, and is also a promising treatment target. Similarly, stress shows a complex relationship with the circadian system. The CLOCK gene, encoding a key element in circadian regulation has been implicated in previous candidate variant studies in depression with contradictory findings, and only a few such studies considered the interacting effects of stress. We investigated the effect of CLOCK variation with a linkage-disequilibrium-based clumping method, in interaction with childhood adversities and recent negative life events, on two phenotypes of depression, lifetime depression and current depressive symptoms in a general population sample.Methods: Participants in NewMood study completed questionnaires assessing childhood adversities and recent negative life events, the Brief Symptom Inventory to assess current depressive symptoms, provided data on lifetime depression, and were genotyped for 1054 SNPs in the CLOCK gene, 370 of which survived quality control and were entered into linear and logistic regression models with current depressive symptoms and lifetime depression as the outcome variable, and childhood adversities or recent life events as interaction variables followed by a linkage disequilibrium-based clumping process to identify clumps of SNPs with a significant main or interaction effect.Results: No significant clumps with a main effect were found. In interaction with recent life events a significant clump containing 94 SNPs with top SNP rs6825994 for dominant and rs6850524 for additive models on current depression was identified, while in interaction with childhood adversities on current depressive symptoms, two clumps, both containing 9 SNPs were found with top SNPs rs6828454 and rs711533.Conclusion: Our findings suggest that CLOCK contributes to depressive symptoms, but via mediating the effects of early adversities and recent stressors. Given the increasing burden on circadian rhythmicity in the modern lifestyle and our expanding insight into the contribution of circadian disruption in depression especially as a possible mediator of stress, our results may pave the way for identifying those who would be at an increased risk for depressogenic effects of circadian dysregulation in association with stress as well as new molecular targets for intervention in stress-related psychopathologies in mood disorders.

Background: Suboptimal treatment response during anti-depressive treatment is fairly common with the first antidepressant (AD) choice, followed by switching to another agent in the majority of cases. However, the efficacy of this strategy over continuation of the original agent is less solidly documented in real-life studies. The aim of our present study was to ascertain the effects of switching to duloxetine following inadequate response to prior ADs on general illness severity, pain, and health-related quality of life in a large sample of major depressive disorder (MDD) and generalized anxiety disorder (GAD) patients in a prospective, real-world, multicenter, observational study.Methods: A total of 578 participants with MDD or GAD were enrolled in 58 outpatient sites in an 8-week, single-arm, open-label, flexible-dose trial with duloxetine. Severity of symptoms [with Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I)], severity of pain (with a Visual Analog Scale), satisfaction with current treatment, and health-related quality of life [with the three-level version of the EuroQol five-dimensional questionnaire (EQ-5D-3L)] measures were recorded at baseline and at follow-up visits 4 and 8 weeks after initiation of treatment. Data were analyzed using ANOVA and mixed linear models.Results: 565 patients completed the study and comprised the analyzed dataset. Results indicated that severity of illness significantly decreased over the 8 weeks of the study and already at 4 weeks in both patient groups. Overall quality of life and all of its subindicators also significantly improved in both patient groups and so did subjective experience of pain. Satisfaction with current treatment also significantly increased during the study period. Frequency of side effects was low. In both GAD and MDD groups, two patients dropped out of the study due to adverse effects, leading to treatment termination in four cases (0.7%).Conclusions: This 8-week, multicenter, flexible-dosing, single-arm, open-label, observational real-life study in MDD and GAD patients switched to duloxetine after inadequate response or low tolerability to other ADs showed a significant positive effect on all outcome measures, including a significant decrease in illness severity as well as significant overall symptomatic improvement, with good tolerability.

Abstract Background Although there are several models on the structure of human temperament, character and personality, the majority follow a single approach, providing a unilateral and overly theoretical construct which is unsuitable for clinical application. The current study aimed to develop a complex and comprehensive model of temperament and character by empirically combining relevant existing theories. Methods The study included 734 healthy general population subjects aged 40.80 ± 11.48 years, who completed the TEMPS-A, TCI and NEO-PI-3 questionnaires. Data were analyzed in a multistep approach using Exploratory Factor analysis and forward stepwise linear regression. Results The results yielded two highest order factors (Self and Self–Environment Interaction), six middle order factors (Emotional Self, Cognitive Self, Social Emotionality, Emotional and Cognitive Control, Ethical Emotionality and Behavior, Social Emotionality and Behavior) and 12 factors at the bottom (Ego Resiliency, Ego Strength, Intrapersonal Emotion, Personal Space Cognition, Interpersonal Cognition, Emotional Creativity, Externalized Interpersonal Emotion, Internalized Interpersonal Emotion, Emotional Motivation, Self-Discipline, Ethical Values and Ethical Behavior). Conclusions The current study developed a complex hierarchical model of temperament and character on the basis of empirical data from several temperament theories. An important feature of the new temperamental model is the frequent admixture of emotional and cognitive processes within the same module. This model expands the field to include elements probably corresponding to meta-cognition mechanisms and complex interactions between affective and cognitive control, which may provide useful in understanding and treating affective disorders as well.

The P2X purinoceptor 7 (P2RX7) mediates inflammatory microglial responses and is implicated in neuroimmune mechanisms of depression and neurodegenerative disorders. A number of studies suggest that psychosocial stress may precipitate depression through immune activation. Genetic association studies of P2RX7 variants with depression have been inconclusive. However, nearly all studies have focused on only one single-nucleotide polymorphism (SNP) and have not considered interaction with psychosocial stress. We investigated the effect of several variations in P2RX7 gene using a clumping method in interaction with early adversities and recent stress on depression severity. 1752 subjects provided information on childhood adversities, recent life events, and current depression severity. Participants were genotyped for 681 SNPs in the P2RX7 gene, 335 of them passed quality control and were entered into linear regression models followed by a clumping procedure for main effect and interactions. No significant main effect was observed. Rs74892325 emerged as a top SNP for interaction with childhood adversities and rs61953400 for interaction with recent life events. Our study is the first to investigate several variants in the P2RX7 gene and in interaction with two types of stress, extending our understanding of neuroinflammation in depression, and supporting that the majority of genes influence depression by enhancing sensitivity to stressors.

BackgroundStressful life events (SLE) may influence the illness course and outcome. This study aimed to characterize socio-demographic and clinical features of euthymic major depressive disorder (MDD) outpatients with SLE compared with those without.MethodsThe present sample included 628 (mean age=55.1 ± 16.1) currently euthymic MDD outpatients of whom 250 (39.8%) reported SLE and 378 (60.2%) did not.ResultsAfter univariate analyses, outpatients with SLE were most frequently widowed and lived predominantly with friends/others. Moreover, relative to outpatients without SLE, those with SLE were more likely to have a family history of suicidal behavior, manifested melancholic features, report a higher Coping Orientation to the Problems Experienced (COPE) positive reinterpretation/growth and less likely to have a comorbid panic disorder, residual interepisodic symptoms, use previous psychiatric medications, and currently use of antidepressants. Having a family history of suicide (OR=9.697; p=≤.05), history of psychotropic medications use (OR=2.888; p=≤.05), and reduced use of antidepressants (OR=.321; p=.001) were significantly associated with SLE after regression analyses. Mediation analyses showed that the association between current use of antidepressants and SLE was mediated by previous psychiatric medications.ConclusionHaving a family history of suicide, history of psychotropic medications use, and reduced use of antidepressants is linked to a specific “at risk” profile characterized by the enhanced vulnerability to experience SLE.

BackgroundLack of proper consideration of the interaction between biological and environmental factors limits our understanding of the development of depression. Our cross-sectional study investigated whether recent stress influences the effect of affective temperaments on depressive symptoms.Methods1015 general population participants completed the Brief Symptom Inventory to capture depressive symptoms, the List of Threatening Experiences Questionnaire to assess recent stressors, and the Temperament Evaluation of Memphis Pisa, Paris, and San Diego Autoquestionnaire to evaluate affective temperaments (TEMPS-A). Linear regression models were built to investigate the effect of temperament and stress on depression, temperament on stress, and the effect of temperament on depressive symptoms in different stress exposure groups.ResultsRecent life events and anxious, depressive, cyclothymic, and hyperthymic temperaments significantly predicted depressive symptoms, and cyclothymic, and hyperthymic temperaments significantly predicted recent life event exposure. While in case of mild stress all affective temperaments except irritable predicted depression, in case of moderate exposure only the effect of depressive, cyclothymic, and hyperthymic temperament, while in the high exposure group only the effect of anxious temperament was significant.LimitationsAll measures were based on self-report, and subjective impact of life events was not considered. This was a cross-sectional study with a correlational nature which does not allow for causative conclusions.ConclusionsThe contribution of affective temperaments to depression is much higher compared to stress, and severity of exposure to life events influences the impact of affective temperaments on depressive symptoms, pointing to divergent pathways of emotional reactivity mediating the effects of stress on depression which can be exploited for prevention and treatment.

BackgroundSuicide is an unresolved psychiatric and public health emergency, claiming 800,000 lives each year, however, its neurobiological etiology is still not understood. In spite of original reports concerning the involvement of 5-HTTLPR in interaction with recent stress in the appearance of suicidal ideation and attempts, replication studies have yielded contradictory results. In our study, we analyzed the association between 5-HTTLPR and lifetime suicide attempts, current suicidal ideation, hopelessness and thoughts of death as main effects, and in interaction with childhood adversities, recent stress, and different types of recent life events in a general population sample.MethodsTwo thousand and three hundred fifty-eight unrelated European volunteers were genotyped for 5-HTTLPR, provided phenotypic data on previous suicide attempts, and current suicidal ideation, hopelessness and thoughts about death, and information on childhood adversities and recent life events. Logistic and linear regression models were run with age, gender, and population as covariates to test for the effect of 5-HTTLPR as a main effect and in interaction with childhood adversities and recent life events on previous suicide attempts and current suicidal ideation. Benjamini-Hochberg FDR Q values were calculated to correct for multiple testing.Results5-HTTLPR had no significant effect on lifetime suicide attempts either as a main effect on in interaction with childhood adversities. 5-HTTLPR had a significant main effect on current suicidal ideation in the dominant model (Q=0.0344). 5-HTTLPR did not interact with childhood adversities or total number of recent life events on any phenotypes related to current suicidal risk, however, a significant interaction effect between 5-HTTLPR and current relationship problems emerged in the case of current suicidal ideation in the dominant model (Q=0.0218) and in the case of thoughts about death and dying in the dominant (Q=0.0094) and additive models (Q=0.0281).ConclusionWhile 5-HTTLPR did not influence previous suicide attempts or interacted with childhood adversities, it did influence current suicidal ideation with, in addition, an interaction with recent relationship problems supporting the involvement of 5-HTTLPR in suicide. Our findings that 5-HTTLPR impacts only certain types of suicide risk-related behaviors and that it interacts with only distinct types of recent stressors provides a possible explanation for previous conflicting findings.

Background: Affective temperaments (depressive, irritable, hyperthymic, anxious, cyclothymic) have important role in psychopathology, but cumulating data support their involvement in vascular pathology, especially in hypertension as well. The aim of our study was to evaluate their associations with 24-hour brachial and central hemodynamic parameters in untreated patients who were studied because of elevated office blood pressure. Methods: Mobil-O-Graph was used to measure the 24-hour brachial and central parameters. Affective temperaments, depression and anxiety were evaluated with TEMPS-A, Beck and HAMA questionnaires, respectively. Results: 84 patients were involved into the study (49 men). Irritable temperament score was associated with nighttime brachial systolic blood pressure (r = 0.279, p = 0.010), with nighttime brachial mean arterial pressure (r = 0.239, p = 0.028), with nighttime central systolic blood pressure (r = 0.288, p = 0.008), with nighttime central diastolic blood pressure (r = 0.238, p = 0.029), with 24-hour cardiac output (r = 0.298, p = 0.006) and inversely with 24-hour reflection magnitude (r = −0.297, p = 0.006). These associations were attenuated after the adjustment of age, depression and anxiety and were absent in women. Conclusion: In conclusion, affective temperaments, especially irritable temperament can have an impact on 24-hour brachial and central hemodynamics in untreated hypertensive men.

From the end of the 1980s, the Hungarian suicide rate, which had been until that point the highest in the world for decades, has decreased drastically. The reason behind this decrease was probably due to the changes in numerous and often interlinked risk factors. Studies on this topic have mostly ignored to interrogate to what extent the change of the population composition, for example the improvement of educational level, contributed to the decrease of the rate in the given period? Our aim was to assess the contribution of changes in some sociodemographic factors to the decrease of the suicide rate in Hungary. During the analysis, data from 1990 were compared with data from 2011. For the statistical calculations, the method of "Standardization and Decomposition (SDA)" was used, which according to our best knowledge, has not yet been applied in Hungarian suicide studies. The results show that the improvement of educational level helped to decrease the rate for men by about a third, while for women only by about a tenth. However, the benefit of the improvement in educational attainment during the period investigated was significantly offset by the changes primarily in marital status (the ratios of unmarried and divorced subjects increased for both genders) and in age distribution (the ratio of the elderly persons increased for both genders). The results of our study emphasise the inverse relationship between suicide and educational level and support the hypothesis that we can regard educational policy as indirect health policy.

Previous studies suggested that both maladaptive stress response and circadian dysregulation might have a role in the background of migraine. However, effects of circadian genes on migraine have not been tested yet. In the present study, we investigated the main effect of rs10462028 of the circadian locomotor output cycles kaput (CLOCK) gene and its interaction with different stress factors on migraine. In our cross-sectional study 2,157 subjects recruited from Manchester and Budapest completed the ID-Migraine questionnaire to detect migraine type headaches (migraineID). Additional stress factors were assessed by a shortened version of the Childhood Trauma Questionnaire, the List of Threatening Experiences questionnaire, and a validated questionnaire to identify financial difficulties. Rs10462028 showed no main genetic effect on migraineID. However, chronic stress indexed by financial difficulties showed a significant interaction effect with rs10462028 (p = 0.006 in recessive model) on migraineID. This result remained significant after correction for lifetime bipolar and unipolar depression and was replicated in both subsamples, although only a trend effect was reached after Bonferroni-correction, which is the strictest correction not considering interdependences. Childhood adversity (CHA) and Recent negative life events (RLE) showed no significant gene × stress interaction with rs10462028. In addition, in silico analysis demonstrated that the genetic region tagged by rs10462028 alters the binding of several miRNAs. Our exploratory study suggests that variations in the CLOCK gene, with moderating effect on gene function through miRNA binding, in interaction with financial difficulties might influence the risk of migraine-type headaches. Thus, financial hardship as a chronic stress factor may affect migraine through altering circadian rhythms.

Past-oriented rumination and future-oriented worry are two aspects of perseverative negative thinking related to the neuroticism endophenotype and associated with depression and anxiety. Our present aim was to investigate the genomic background of these two aspects of perseverative negative thinking within separate groups of individuals with suboptimal versus optimal folate intake. We conducted a genome-wide association study in the UK Biobank database (n = 72,621) on the “rumination” and “worry” items of the Eysenck Personality Inventory Neuroticism scale in these separate groups. Optimal folate intake was related to lower worry, but unrelated to rumination. In contrast, genetic associations for worry did not implicate specific biological processes, while past-oriented rumination had a more specific genetic background, emphasizing its endophenotypic nature. Furthermore, biological pathways leading to rumination appeared to differ according to folate intake: purinergic signaling and circadian regulator gene ARNTL emerged in the whole sample, blastocyst development, DNA replication, and C-C chemokines in the suboptimal folate group, and prostaglandin response and K+ channel subunit gene KCNH3 in the optimal folate group. Our results point to possible benefits of folate in anxiety disorders, and to the importance of simultaneously taking into account genetic and environmental factors to determine personalized intervention in polygenic and multifactorial disorders.

The serotonin system has been suggested to moderate the association between childhood maltreatment and rumination, with the latter in its turn reported to be a mediator in the depressogenic effect of childhood maltreatment. Therefore, we investigated whether the associations of two epigenetic regulatory polymorphisms in the HTR2A serotonin receptor gene with Ruminative Responses Scale rumination and its two subtypes, brooding and reflection, are moderated by childhood adversity (derived from the Childhood Trauma Questionnaire) among 1,501 European white adults. We tested post hoc whether the significant associations are due to depression. We also tested the replicability of the significant results within the two subsamples of Budapest and Manchester. We revealed two significant models: both the association of methylation site rs6311 with rumination and that of miRNA binding site rs3125 (supposed to bind miR-1270, miR-1304, miR-202, miR-539 and miR-620) with brooding were a function of childhood adversity, and both interaction findings were significantly present both in the never-depressed and in the ever-depressed group. Moreover, the association of rs3125 with brooding could be replicated across the separate subsamples, and remained significant even when controlling for lifetime depression and the Brief Symptom Inventory depression score. These findings indicate the crucial importance of involving stress factors when considering endophenotypes and suggest that brooding is a more promising endophenotype than a broader measure of rumination. Transdiagnostic relevance of the brooding endophenotype and the potential of targeting epigenetic regulatory polymorphisms of HTR2A in primary and secondary prevention of depression and possibly of other disorders are also discussed.

Environmental stress and its interaction with genetic variation are key contributors in the development of depression and anxiety, yet there is a failure to identify replicable genetic variants and gene-interaction effects in the background of these psychiatric symptoms. Recently it has been reported that 5-HTTLPR and NOSI interact with financial but not other types of recent stressors in the development of depression. In the present study we investigated the interaction of GABRA6 rs3219151 and CNR1 rs7766029 in interaction with different types of recent life events on the presence of depression and anxiety in a large general population sample. 2191 participants completed the List of Threatening Experiences questionnaire which covers four categories of stressful life events (financial problems, illness/personal problems, intimate relationships, and social network) experienced over the previous year and the Brief Symptom Inventory for depression and anxiety symptoms. Participants were genotyped for rs3219151 and rs7766029. Data were analyzed with linear regression models with age and gender as covariates. Results indicated that CNR1 rs7766029 interacted significantly with financial but not other types of life events both in case of depression and anxiety symptoms. In contrast, GABRA6 rs3219151 showed a significant interaction with social network related life events in case of anxiety and with illness/personal problem-related life events in case of depression. Our results suggest that the psychological impact of different types of recent stress may be differentially modulated by distinct molecular genetic pathways. Furthermore, in case of certain genetic variants, the occurring psychiatric symptom may depend on the type of stress experienced.

Background and Objectives: The role of affective temperament in the genesis and outcome of major mood disorders is well studied, but there are only a few reports on the relationship between panic disorder (PD) and affective temperaments. Accordingly, we aimed to study the distribution of affective temperaments (depressive (DE); cyclothymic (CT); irritable (IRR); hyperthymic (HT) and anxious (ANX)) among outpatients with PD. Materials and Methods: Affective temperaments of 118 PD outpatients (80 females and 38 males) with or without agoraphobia but without any other psychiatric disorder at the time of inclusion were evaluated using the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) and compared with the affective temperament scores of control subjects. All patients were followed up for at least 1.5 years in order to detect the onset of any major affective disorders, substance use disorders and suicide attempts. Results: Among females, the dominant ANX and DE temperaments were four and three times as common as in a large normative Hungarian sample (for both cases p < 0.01). Among male PD patients, only the dominant DE temperament was slightly overrepresented in a non-significant manner. Females with PD obtained significantly higher scores on ANX, DE and CT subscales of the TEMPS-A, whereas males with PD showed significantly higher scores on ANX, DE and HT temperament subscales compared with the members of a large normative Hungarian sample and also with a gender- and age-matched control group. During the follow-up, newly developed unipolar major depression and bipolar spectrum (bipolar I or II and cyclothymic) disorders appeared in 64% and 22% of subjects, respectively. Conclusions: Our preliminary findings suggest that a specific, ANX-DE-CT affective temperament profile is characteristic primarily for female patients, and an ANX-DE-HT affective temperament profile is characteristic for male patients with PD, respectively. These findings are in line with expectations because PD is an anxiety disorder par excellence on the one hand, whereas, on the other hand, it is quite frequently comorbid with mood (including bipolar) disorders.

Temperaments are imperturbable variations of personality, traits and ways of reacting to the environment that characterize individuals and remain constant throughout several different situations. Temperaments usually play a central role in determining emotional reactions, therefore several temperamental models have attempted to establish the potential relationship between temperaments and affective disorders. According to Hagop Akiskal, affective temperaments are subclinical and subaffective trait-like manifestations of affective disorders. Unlike several models of temperament which were exclusively developed theoretically in order to describe healthy human functioning, later extrapolated to capture the pathological domains of mental and behavioral features, the current model of affective temperaments was developed on classical traditions and mainly based on the observation of subjects with mood disorders and their healthy first degree relatives. There is accumulating evidence concerning the development of affective temperaments based on their adaptive evolutionary characteristics and genetic background, and normative data from large national studies on general and healthy samples indicate their universal characteristics. Studies in affective patient populations indicate that the relationship between affective temperaments and affective illness is more complex than a simple extrapolation from psychopathology and mental health, and affective temperaments may represent a latent state of the staging model, playing a pathoplastic role in mood disorders determining their evolution, clinical features, main characteristics and outcome. A large body of data on affective temperaments has been published during the last decade, deserving a critical analysis presented in this overview.

It is well known that alexithymic individuals may show significantly higher levels of anxiety, depression, and psychological suffering than non-alexithymics. There is an increasing evidence that alexithymia may be considered a risk factor for suicide, even simply increasing the risk of development of depressive symptoms or per se. Therefore, the purpose of this narrative mini-review was to elucidate a possible relationship between alexithymia and suicide risk. The majority of reviewed studies pointed out a relationship between alexithymia and an increased suicide risk. In several studies, this relationship was mediated by depressive symptoms. In conclusion, the importance of alexithymia screening in everyday clinical practice and the evaluation of clinical correlates of alexithymic traits should be integral parts of all disease management programs and, especially, of suicide prevention plans and interventions. However, limitations of studies are discussed and must be considered.

IntroductionMigraine and depression frequently occur as comorbid conditions, and it has been hypothesized that migraine with and without depression may have a different genetic background. A distinct personality trait constellation has been described in migraineurs. Less attention, however, was paid to personality differences in migraineurs with and without depression which may also shed light on differences in the neurobiological, background. The aim of our study was to investigate big five personality traits, headaches, and lifetime depression (DEP) in a large European general population sample.MethodsRelationship between DEP, Big Five Inventory personality traits, and headaches identified by the ID-Migraine Questionnaire were investigated in 3,026 individuals from Budapest and Manchester with multivariate and logistic regression analyses.ResultsBoth DEP and migraine(ID) showed differences in personality traits. Neuroticism was an independent risk factor for both conditions while a significant interaction effect appeared between the two in the case of openness. Namely, subjects with migraine(ID) and without DEP scored higher on openness compared to those who had depression.ConclusionWhile we confirmed previous results that high neuroticism is a risk factor for both depression and migraine, openness to experience was significantly lower in the co-occurrence of migraine and depression. Our results suggest that increased openness, possibly manifested in optimal or advantageous cognitive processing of pain experience in migraine may decrease the risk of co-occurrence of depression and migraine and thus may provide valuable insight for newer prevention and intervention approaches in the treatment of these conditions.

Bipolar disorders (BDs) are prevalent mental health illnesses that affect about 1−5% of the total population, have a chronic course and are associated with a markedly elevated premature mortality. One of the contributors for the decreased life expectancy in BD is suicide. Accordingly, the rate of suicide among BD patients is approximately 10−30 times higher than the corresponding rate in the general population. Extant research found that up to 20% of (mostly untreated) BD subjects end their life by suicide, and 20−60% of them attempt suicide at least one in their lifetime. In our paper we briefly recapitulate the current knowledge on the epidemiological aspects of suicide in BD as well as factors associated with suicidal risk in BD. Furthermore, we also discuss concisely the possible means of suicide prevention in BD.

Objective: To compare sensory processing, coping strategies, and quality of life (QoL) in unipolar and bipolar patients; to examine correlations between sensory processing and QoL; and to investigate the relative contribution of sociodemographic characteristics, sensory processing, and coping strategies to the prediction of QoL. Methods: Two hundred sixty-seven participants, aged 16-85 years (53.6±15.7), of whom 157 had a diagnosis of unipolar major depressive disorder and 110 had bipolar disorder type I and type II, completed the Adolescent/Adult Sensory Profile, Coping Orientations to Problems Experienced, and 12-item Short-Form Health Survey version 2. The two groups were compared with multivariate analyses. Results: The unipolar and bipolar groups did not differ concerning sensory processing, coping strategies, or QoL. Sensory processing patterns correlated with QoL independently of mediation by coping strategies. Correlations between low registration, sensory sensitivity, sensation avoidance, and reduced QoL were found more frequently in unipolar patients than bipolar patients. Higher physical QoL was mainly predicted by lower age and lower sensory sensitivity, whereas higher mental QoL was mainly predicted by coping strategies. Conclusion: While age may predict physical QoL, coping strategies predict mental QoL. Future studies should further investigate the impact of sensory processing and coping strategies on patients’ QoL in order to enhance adaptive and functional behaviors related to affective disturbances.

OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis.OBJETIVO: Os autores apresentam um modelo de transtorno do pânico que se baseia nos efeitos da hiperventilação aguda e crônica, característicos do subtipo respiratório de transtorno do pânico. O modelo é generalizado a partir desses efeitos. Ele integra três características da hiperventilação: a hiperventilação é uma resposta fisiológica à hipercapnia; a hiperventilação pode induzir ataques de pânico; a hiperventilação crônica representa um mecanismo protetor contra os ataques de pânico. MÉTODO: Revisão seletiva da literatura a partir da base de dados Medline. Foram selecionados relatos referentes à inter-relação entre transtorno do pânico, hiperventilação, acidose, alcalose, liberação de catecolaminas e sensibilidade a catecolaminas, sendo os achados estruturados de modo a formar um modelo integrado. DISCUSSÃO: Os ataques de pânico do transtorno do pânico desenvolvem-se com base numa acidose metabólica, que é uma resposta compensatória à hiperventilação crônica. Os ataques são desencadeados por um súbito aumento da pressão parcial de dióxido de carbono (pCO2), quando a acidose (metabólica) latente se manifesta pela acidose hipercápnica. A condição acidótica induz liberação de catecolaminas. A simpaticotonia não pode manifestar-se durante a fase de hipercapnia, pois o baixo pH diminui a sensibilidade às catecolaminas. As catecolaminas podem provocar pânico quando a hipercapnia comuta para uma alcalose hipocápnica devido à supercompensação pela hiperventilação, situação na qual a sensibilidade às catecolaminas liberadas começa a aumentar. CONCLUSÃO: As abordagens terapêuticas deveriam voltar-se para a regulação em longo prazo do padrão respiratório e a eliminação da acidose metabólica.

Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals.Our study is cross-sectional and applies self-report questionnaires.Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.

The purpose of this study was to test the validity of affective temperaments for predicting psychiatric morbidity and suicide risk, using a two-factor model to explain the relationships between temperament, anxiety, depression, and hopelessness. We investigated 210 high school students, 103 males and 107 females, 18-19 years old, who were administered self-report questionnaires to assess temperament (TEMPS-A), depression (BDI-II), anxiety (STAI) and hopelessness (BHS). The final structural model had a good fit with the data, with two factors significantly correlated, the first labeled unstable cyclothymic temperament including Dysthymic/Cyclothymic/Anxious temperament, Irritable temperament and Depression, and the second labeled Demoralization including Anxiety (State/Trait) and Hopelessness. Depression, anxiety and hopelessness are in a complex relationship partly mediated by temperament.

The complex relationship between the use of antidepressants and suicidal behaviour is one of the hottest topics of our contemporary psychiatry. Based on the literature, this paper summarizes the author's view on antidepressant-resistant depression and antidepressant-associated suicidal behaviour. Antidepressant-resistance, antidepressant-induced worsening of depression, antidepressant-associated (hypo)manic switches, mixed depressive episode, and antidepressant-associated suicidality among depressed patients are relatively most frequent in bipolar/bipolar spectrum depression and in children and adolescents. As early age at onset of major depressive episode and mixed depression are powerful clinical markers of bipolarity and the manic component of bipolar disorder (and possible its biological background) shows a declining tendency with age antidepressant-resistance/worsening, antidepressant-induced (hypo)manic switches and “suicide-inducing” potential of antidepressants seem to be related to the underlying bipolarity.