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Background: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are associated, but it is unclear if this is a causal relationship or confounding. We used genetic analyses and sibling comparisons to clarify the direction of this relationship. Methods: Linkage disequilibrium score regression and 2-sample Mendelian randomization were used to test for genetic correlation (r g) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and 6 PTSD definitions (up to 320,369 individuals). Several additional variables were included in the analysis to verify the independence of the ADHD-PTSD relationship. In a population-based sibling comparison (N = 2,082,118 individuals), Cox regression models were fitted to account for time at risk, a range of sociodemographic factors, and unmeasured familial confounders (via sibling comparisons). Results: ADHD and PTSD had consistent r g (r g range, 0.43–0.52; p < .001). ADHD genetic liability was causally linked with increased risk for PTSD (β = 0.367; 95% CI, 0.186–0.552; p = 7.68 × 10 −5). This result was not affected by heterogeneity, horizontal pleiotropy (Mendelian randomization Egger intercept = 4.34 × 10 −4, p = .961), or other phenotypes and was consistent across PTSD datasets. However, we found no consistent associations between PTSD genetic liability and ADHD risk. Individuals diagnosed with ADHD were at a higher risk for developing PTSD than their undiagnosed sibling (hazard ratio = 2.37; 95% CI, 1.98–3.53). Conclusions: Our findings add novel evidence supporting the need for early and effective treatment of ADHD, as patients with this diagnosis are at significantly higher risk to develop PTSD later in life.

Objectives Posttraumatic stress disorder (PTSD) is triggered by extremely stressful environmental events and characterized by high emotional distress, re-experiencing of trauma, avoidance and hypervigilance. The present study uses polygenic risk scores (PRS) derived from the UK Biobank (UKBB) mega-cohort analysis as part of the PGC PTSD GWAS effort to determine the heritable basis of PTSD in the South Eastern Europe (SEE)-PTSD cohort. We further analyzed the relation between PRS and additional disease-related variables, such as number and intensity of life events, coping, sex and age at war on PTSD and CAPS as outcome variables. Methods Association of PRS, number and intensity of life events, coping, sex and age on PTSD were calculated using logistic regression in a total of 321 subjects with current and remitted PTSD and 337 controls previously subjected to traumatic events but not having PTSD. In addition, PRS and other disease-related variables were tested for association with PTSD symptom severity, measured by the Clinician Administrated PTSD Scale (CAPS) by liner regression. To assess the relationship between the main outcomes PTSD diagnosis and symptom severity, each of the examined variables was adjusted for all other PTSD related variables. Results The categorical analysis showed significant polygenic risk in patients with remitted PTSD and the total sample, whereas no effects were found on symptom severity. Intensity of life events as well as the individual coping style were significantly associated with PTSD diagnosis in both current and remitted cases. The dimensional analyses showed as association of war-related frequency of trauma with symptom severity, whereas the intensity of trauma yielded significant results independently of trauma timing in current PTSD. Conclusions The present PRS application in the SEE-PTSD cohort confirms modest but significant polygenic risk for PTSD diagnosis. Environmental factors, mainly the intensity of traumatic life events and negative coping strategies, yielded associations with PTSD both categorically and dimensionally with more significant p-values. This suggests that, at least in the present cohort of war-related trauma, the association of environmental factors and current individual coping strategies with PTSD psychopathology was stronger than the polygenic risk.

Background Cerebrospinal levels of isoprostanes (IsoPs) have been established as biomarkers of oxidative stress in Alzheimer's disease (AD) and vascular dementia (VD). The value of peripheral levels in the diagnostics of these diseases is less conclusive. The aim of this study was to determine serum 8-iso-prostaglandin-F2alpha (8-iso-PGF2α) levels in Bosnian AD and VD patients and to establish whether there is an association between 8-iso-PGF2α serum concentration and cognitive impairment (CI) in patients with dementia. Subjects and methods Serum levels of 8-iso-PGF2α were measured by enzyme immunoassay method in AD (n=30) and VD patients (n=30) and control subjects (CG, n=30). The AD and VD group were further stratified according to the level of CI. Results The serum 8-iso-PGF2α levels were significantly higher in the AD (74.00 pg/mL) and VD groups (38.00 pg/mL) compared to the CG (17.50 pg/mL). A significant difference in serum 8-iso-PGF2α levels between patients with moderate and severe CI was not established in either AD or VD. Conclusion Serum 8-iso-PGF2α proved to be a good biomarker in AD and VD, however it cannot be recommended for the differentiation of moderate and severe CI.

Funding Information: This work was supported by the National Institute of Mental Health / U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium ), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience . Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. Funding Information: MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc., RallyPoint Networks, Inc., Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was supported by the National Institute of Mental Health/ U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, IL, MBS, KJRe, and KCK], National Institutes of Health (Grant No. 5U01MH109539 to the Psychiatric Genomics Consortium), and Brain & Behavior Research Foundation (Young Investigator Grant [to KWC]). Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience. Statistical analyses were carried out on the LISA/Genetic Cluster Computer (https://userinfo.surfsara.nl/systems/lisa) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). This work would have not been possible without the financial support provided by Cohen Veterans Bioscience, the Stanley Center for Psychiatric Genetics at the Broad Institute, and One Mind. This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the U.S. Department of the Army or the Department of Defense. We thank the investigators who comprise the PGC-PTSD working group and especially the more than 206,000 research participants worldwide who shared their life experiences and biological samples with PGC-PTSD investigators. We thank Mark Zervas for his critical input. Full acknowledgments are in Supplement 1. MBS has in the past 3 years received consulting income from Actelion, Acadia Pharmaceuticals, Aptinyx, Bionomics, BioXcel Therapeutics, Clexio, EmpowerPharm, GW Pharmaceuticals, Janssen, Jazz Pharmaceuticals, and Roche/Genentech and has stock options in Oxeia Biopharmaceuticals and Epivario. In the past 3 years, NPD has held a part-time paid position at Cohen Veterans Bioscience, has been a consultant for Sunovion Pharmaceuticals, and is on the scientific advisory board for Sentio Solutions for unrelated work. In the past 3 years, KJRe has been a consultant for Datastat, Inc. RallyPoint Networks, Inc. Sage Pharmaceuticals, and Takeda. JLM-K has received funding and a speaking fee from COMPASS Pathways. MU has been a consultant for System Analytic. HRK is a member of the Dicerna scientific advisory board and a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which during the past 3 years was supported by Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Dicerna, Ethypharm, Indivior, Lundbeck, Mitsubishi, and Otsuka. HRK and JG are named as inventors on Patent Cooperative Treaty patent application number 15/878,640, entitled ?Genotype-guided dosing of opioid agonists,? filed January 24, 2018. RP and JG are paid for their editorial work on the journal Complex Psychiatry. OAA is a consultant to HealthLytix. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. publishersversion published

Funding Information: This work was supported by the National Institute of Mental Health/U.S. Army Medical Research and Development Command (Grant No. R01MH106595 [to CMN, MBS, KJRe, and KCK]), and National Institutes of Health (Grant No. 5U01MH109539 [to the Psychiatric Genomics Consortium] and Grant No. U19 MH069056 [to BWD])). Financial support for the PTSD PGC was provided by the Cohen Veterans Bioscience, Stanley Center for Psychiatric Research at the Broad Institute, and One Mind. Genotyping of samples was provided in part through the Stanley Center for Psychiatric Genetics at the Broad Institute supported by Cohen Veterans Bioscience Statistical analyses were carried out on the LISA/Genetic Cluster Computer ( https://userinfo.surfsara.nl/systems/lisa ) hosted by SURFsara. This research has been conducted using the UK Biobank resource (Application No. 41209). Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10−8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further. publishersversion published

Background: Negative symptoms are core features of schizophrenia and very challenging to be treated. Identification of their structure is crucial to provide a better treatment. Increasing evidence supports the superiority of a five-factor model (alogia, blunted affect, anhedonia, avolition, and asociality as defined by the NMIH-MATRICS Consensus); however, previous data primarily used the Brief Negative Symptoms Scale (BNSS). This study, including a calibration and a cross-validation sample (n = 268 and 257, respectively) of participants with schizophrenia, used the Clinical Assessment Interview for Negative Symptoms (CAINS) to explore the latent structure of negative symptoms and to test theoretical and data-driven (from this study) models of negative symptoms. Methods: Exploratory factor analysis (EFA) was carried out to investigate the structure of negative symptoms based on the CAINS. Confirmatory factor analysis (CFA) tested in a cross-validation sample four competing theoretical (one-factor, two-factor, five-factor, and hierarchical factor) models and two EFA-derived models. Result: None of the theoretical models was confirmed with the CFA. A CAINS-rated model from EFA consisting of five factors (expression, motivation for recreational activities, social activities, vocational, and close/intimate relationships) was an excellent fit to the data (comparative fix index = 0.97, Tucker–Lewis index = 0.96, and root mean square error of approximation = 0.07). Conclusions: This study cannot support recent data on the superiority of the five-factor model defined by the NMIH-MATRICS consensus and suggests that an alternative model might be a better fit. More research to confirm the structure of negative symptoms in schizophrenia, and careful methodological consideration, should be warranted before a definitive model can put forward and shape diagnosis and treatment of schizophrenia

Objectives Psychotic disorders have large treatment gap in low- and middle-income countries (LMICs) in South-Eastern Europe, where up to 45% of affected people do not receive care for their condition. This study will assess the implementation of a generic psychosocial intervention called DIALOG+ in mental health care services and its effectiveness at improving patients’ clinical and social outcomes. Methods This is a protocol for a multi-country, pragmatic, hybrid effectiveness–implementation, cluster-randomised, clinical trial. The trial aims to recruit 80 clinicians and 400 patients across 5 South-Eastern European LMICs: Bosnia and Herzegovina, Kosovo*, Montenegro, Republic of North Macedonia and Serbia. Clusters are clinicians working with patients with psychosis, and each clinician will deliver the intervention to five patients. After patient baseline assessments, clinicians will be randomly assigned to either the DIALOG+ intervention or treatment as usual, with an allocation ratio of 1:1. The intervention will be delivered six times over 12 months during routine clinical meetings. TThe primary outcome measure is the quality of life at 12 months [Manchester Short Assessment of Quality of Life (MANSA)]; the secondary outcomes include mental health symptoms [Brief Psychiatric Rating Scale (BPRS), Clinical Assessment Interview for Negative Symptoms (CAINS), Brief Symptom Inventory (BSI)], satisfaction with services [Client Satisfaction Questionnaire (CSQ-8)] and economic costs at 12 months [based on Client Service Receipt Inventory (CSRI), EQ-5D-5L and Recovering Quality of Life (ReQOL-10)]. The study will assess the intervention fidelity and the experience of clinicians and patients’ about implementing DIALOG+ in real-life mental health care settings. In the health economic assessment, the incremental cost-effectiveness ratio is calculated with effectiveness measured by quality-adjusted life year. Data will also be collected on sustainability and reach to inform guidelines for potentially scaling up and implementing the intervention widely. Conclusion: The study is expected to generate new scientific knowledge on the treatment of people with psychosis in health care systems with limited resources. The learning from LMICs could potentially help other countries to expand the access to care and alleviate the suffering of patients with psychosis and their families. Trial registration: ISRCTN 11913964

Introduction: Diabetes and depression are two common and major non-communicable diseases with significant disease burdens worldwide. Aim: The aim of this study is to obtain the association among A1C levels and symptoms of depression in patients with type 2 diabetes in family medicine offices. Methods: This cross-sectional study was carried out between June 2016 and July 2017. We recruited 150 adults with type 2 diabetes from various family medicine offices. The study questionnaire had two parts; the first one for participants and the second one for family medicine physicians. Participants completed the part of the questionnaire with the PHQ-9 scale and questions regarding demographic data. Family medicine physicians completed the part of the questionnaire with questions concerning clinical data. A univariate and multivariate linear regression analysis was conducted to identify significant predictors of depressive symptoms revealed by the PHQ-9 score. Results: Multiple linear regression showed that the level of A1C was a significant predictor of the PHQ-9 score in all three models. Increases in the A1C level were followed by increases in depressive symptoms. Other significant predictors of a positive PHQ-9 score were smoking, level of education and income. Conclusion: The level of A1C as an indicator of glycemic control has been shown to have a significant association with the scores of the PHQ-9 questionnaire, which identifies the intensity of symptoms of depression. An increase in the level of A1C is followed by an increase in the intensity of symptoms of depression.

Background: Implementation of psychosocial interventions in mental health services has the potential to improve the treatment of psychosis spectrum disorders (PSD) in low- and middle-income countries (LMICs) where care is predominantly focused on pharmacotherapy. The first step is to understand the views of key stakeholders. We conducted a multi-language qualitative study to explore the contextual barriers and facilitators to implementation of a cost-effective, digital psychosocial intervention, called DIALOG+, for treating PSD. DIALOG+ builds on existing clinician-patient relationships without requiring development of new services, making it well-fitting for healthcare systems with scarce resources. Methods: Thirty-two focus groups were conducted with 174 participants (patients, clinicians, policymakers and carers), who were familiarized with DIALOG+ through a presentation. The Southeast European LMICs included in this research were: Bosnia and Herzegovina, Kosovo, (Kosovo is referred throughout the text by United Nations resolution) North Macedonia, Montenegro and Serbia. Framework analysis was used to analyse the participants’ accounts. Results: Six major themes were identified. Three themes (Intervention characteristics; Carers’ involvement; Patient and organisational benefits) were interpreted as perceived implementation facilitators. The theme Attitudes and perceived preparedness of potential adopters comprised of subthemes that were interpreted as both perceived implementation facilitators and barriers. Two other themes (Frequency of intervention delivery; Suggested changes to the intervention) were more broadly related to the intervention’s implementation. Participants were exceedingly supportive of the implementation of a digital psychosocial intervention such as DIALOG+. Attractive intervention characteristics, efficient use of scarce resources for its implementation and potential to improve mental health services were seen as the main implementation facilitators. The major implementation barrier identified was psychiatrists’ time constrains.

Background: Posttraumatic stress disorder (PTSD) is a disorder that occurs in some people who have experienced a severe traumatic event. Several genetic studies suggest that gene encoding proteins of catechol O-methyl-transferase (COMT) may be relevant for the pathogenesis of PTSD. Some researchers suggested that the elevation of interleukin-6 (IL6) correlates with major depression and PTSD. The aim of this study was to investigate whether the single nucleotide polymorphisms COMT rs4680 (Val158Met) and IL6 rs1800795 are associated with PTSD and contribute to the severity of PTSD symptoms. Subjects and methods: This study comprised 747 participants that experienced war between 1991 and 1999 in the South Eastern Europe conflicts. COMT rs4680 (Val158Met) and IL6 rs1800795 genotypes were determined in 719 participants (369 with and 350 without PTSD). The Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) questionnaire and the Brief Symptom Inventory (BSI) were used for data collection. Results: Regarding the COMT gene polymorphism, the results of the regression analyses for BSI total score were significant in the lifetime PTSD group in the dominant (P=0.031) and the additive allelic model (P=0.047). Regarding the IL6 gene, a significant difference was found for the recessive model predicting CAPS total score in the lifetime PTSD group (P=0.048), and indicated an association between the C allele and higher CAPS scores. n the allelic, genotypic and rezessive model, the results for BSI total score were significant in the lifetime PTSD group (P=0.033, P=0.028 and P=0.009), suggesting a correlation of the C allele with higher BSI scores Conclusion: Although our nominally significant results did not withstand correction for multiple tests they may support a relevance of the COMT (Val158Met) and IL6 rs1800795 polymorphism for aspects of PTSD in war traumatized individuals.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations., Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

Background: Posttraumatic stress disorder (PTSD) is a complex stress related disorder, that follows a severe traumatic experience, characterized with an intense sense of terror, fear, and helplessness. The aim of this study is to identify associations of genetic variations within candidate genes DRD2 and DRD4 with various PTSD related phenotypes. PTSD lifetime and PTSD current subjects were analyzed separately, each of them were analyzed in a Case/Control design, as well as regarding BSI and CAPS within cases only. Subjects and methods: 719 (487 male, 232 female) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Hercegovina, Kosovo and Croatia were included in the study. Sociodemographic questionnaire, Clinician Administered PTSD Scale (CAPS) and the Brief Symptom Inventory (BSI) were used to collect clinical data. Results: The DRD2 rs1800497 variant and a variable number tandem repeat (VNTR) located in exon three of DRD4 were investigated for association with PTSD. In case control analyses we did not identify any significant associations. Within the PTSD current patients, we identified an association of DRD2 rs1800497 with BSI in the genotypic and the recessive model with the T allele as the risk allele. Conclusion: Our findings suggest that rs1800497 of DRD2 gene is involved in pathogenesis of PTSD.

Background: The aim of this study is to investigate the association of gene variations of the monoamine oxidase A (MAOA) and the serotonin transporter solute carrier family 6 member 4 (SLC6A4) gene with posttraumatic stress disorder (PTSD) severity and coping strategies in patients with war related PTSD. Subjects and methods: The study included 747 individuals who had experienced war trauma in the South Eastern Europe conflicts between 1991 and 1999. Genotyping of the MAOA VNTR and SLC6A4 tandem repeat polymorphism in combination with rs25531 was done in 719 participants: 232 females and 487 males. Among them, 369 have had current or lifetime PTSD and 350 have had no PTSD symptoms. For psychometric approach we used the Clinician Administrated PTSD Scale (CAPS), the Brief Symptom Inventory (BSI), the adapted Hoffman Lazarus Coping scale and a basic socio-demographic data questionnaire. Results: There were no significant intergroup (PTSD versus non PTSD) differences in the genotype distribution of MAOA and SLC6A4 gene polymorphisms. The primary finding of our study was that the MAOA short allele (MAOA-S) was nominally significantly associated with the severity of PTSD symptoms in the total subgroup of participants with lifetime PTSD; males for symptoms of hyperarrousal and females with symptoms of re-experience and hyperarousal. In our research the male subsample with current PTSD and MAOA-S genotype had nominally significantly higher scores for some positive coping strategies compared to those carrying the long allele genotype (MAOA-L). There was no significant association between the severity of PTSD symptoms, BSI phenotype, coping scores and the SLC6A4 genotype. Conclusion: The present results support the notion that MAOA VNTR gene variation modulates development and recovery of posttraumatic stress disorder in a war traumatised population, but did not support a connection between SLC6A4 gene variations and war related PTSD.

Background: Posttraumatic stress disorder (PTSD) is an anxiety disorder caused by highly traumatic experiences. The aim of this study was to investigate the influence of single nucleotide polymorphisms (SNPs) in the neuropeptide S receptor 1 (NPSR1) and the glutamate decarboxylase 1(GAD1) gene on PTSD and its psychopathological aspects among individuals affected by the Balkan wars during the 90s. Subjects and methods: This study was conducted as part of the South Eastern Europe (SEE) study on molecular mechanisms of PTSD. It comprised 719 participants (539 males), including those with current PTSD, remitted PTSD and healthy volunteers. Psychometric evaluation was performed using the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS) andthe Brief Symptom Inventory (BSI). We examined NPSR1 single nucleotide polymorphism (SNP) rs324981 and GAD1 variant rs3749034 genotypes. Case-control analyses were carried out using logistical regression to determine genotype differences between all patients that had either current or remitted PTSD and control individuals. To analyse the influence of the analysed SNPs on PTSD severity, we performed linear regression analyses with CAPS and BSI within each of the two patient groups separately. All of the calculations were performed for additive allelic, recessive, dominant and genotypic models. Results: We observed a nominally significant association for the major allele (G) of GAD1 rs3749034 with an increased risk to develop PTSD in a case control analysis in the recessive model (P=0.0315, odds ratio=0.47, SE=0.35). In contrast, a nominally significant association of the minor allele (A) with higher CAPS scores was identified within the patient group with lifetime PTSD in the dominant model (P=0.0372, ????=6.29, SE=2.99). None of these results did withstand correction for multiple tests. No nominal significant results of GAD1 rs3749034 were found with regard to the intensity of psychological BSI symptoms. Case control analyses of NPSR1 rs324981 revealed a nominally significant higher risk for homozygous T allele carriers to develop PTSD (P=0.0452) in the recessive model. On the other hand, the T allele showed a nominally significant association with higher BSI scores in patients suffering from lifetime PTSD in the recessive model (P=0.0434). Again, these results were not significant anymore after correction for multiple tests. No associations of NPSR1 rs324981 and CAPS score was identified. Conclusion: The findings of this study provide some evidence that the NPSR1 and GAD1 polymorphisms might play a role in the development of war-related PTSD and its related psychological expressions. Further research is needed to elucidate the interactions of specific gene variants and environmental factors in the development of PTSD.

Background: Post-traumatic stress disorder (PTSD) is a stress related disorder which can occur in an individual after exposure to a traumatic event. It most commonly co-occurs with depression. The two disorders share not only overlapping symptoms, but also genetic diathesis. The aim of this study was to investigate the potential role of single nucleotide polymorphisms (SNPs) of the two serotonergic candidate genes 5-hydroxytryptamine receptor 1A (HTR1A) and tryptophan hydroxylase 2 (TPH2) in the pathogenesis of PTSD and comorbid psychopathology. Subjects and methods: 719 (487 males, 232 females) participants who had experienced war-related trauma between 1991 and 1999 in Bosnia and Herzegovina, Kosovo and Croatia were included in the study. The Sociodemographic questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I.), Clinician Administered PTSD Scale (CAPS) and Brief Symptom Inventory (BSI) were used to collect clinical data. The SNPs rs6295 (HTR1A), rs11178997 and rs1386494 (TPH2) were investigated for their association with PTSD and comorbid psychopathology. Results: A nominal significant association was found between the BSI total score in Lifetime PTSD with the SNP rs6295 of the HTR1A gene. The best result was seen in the dominant model (P=0.018), with the minor allele (C) being the risk allele. Several BSI subscores were also associated with the minor (C) allele in Lifetime PTSD. No association was found for the TPH2 SNPs rs11178997 and rs1386494 in relation to PTSD or comorbid psychopathology. Conclusions: Our findings suggest that rs6295 in the HTR1A gene may contribute to the psychopathology of PTSD.

Background: Posttraumatic stress disorder (PTSD) is a highly frequent and disabling psychiatric condition among war-affected populations. TheFK506-binding protein 5 (FKBP5) gene and the corticotropin releasing hormone receptor 1 (CRHR1) gene have previously been implicated in an elevated risk of peritraumatic dissociation and PTSD development. Our aim was to investigate the association between FKBP5 and CRHR1 genotypes and PTSD diagnosis and severity among individuals who were affected by the Balkan wars during the 1990s. Subjects and methods: This study included participants with current PTSD, remitted PTSD and healthy volunteers (N=719, 487 males), who were recruited between 2013 and 2015 within the framework of the South Eastern Europe (SEE) - PTSD Study. Psychometric methods comprised the Mini International Neuropsychiatric Interview (M.I.N.I.), the Clinician Administrated PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). FKBP5 rs1360780 and CRHR1 rs17689918 genotypes were determined using a KASP genotyping assay. Results: Tests for deviation from Hardy Weinberg equilibrium showed no significant results. Logistic and linear regression was used to examine the associations between the FKBP5 SNP rs1360780 and the CRHR1 SNP rs17689918 with PTSD diagnosis and severity, as well as general psychiatric symptom severity, separately for current and remitted PTSD patients. There were nominally significant associations under a dominant model between the rs1360780 C allele and PTSD diagnosis as well as symptom severity, which however, were not significant anymore after Bonferroni adjustment (????=0.002). For CRHR1 rs17689918 no significant associations were detected. Conclusion: We found nominally, but not Bonferroni corrected significant associations between the FKBP5 polymorphism rs1360780 and PTSD susceptibility among individuals affected by the Balkan wars. For elucidating this gene’s real resilience/ vulnerability potential, environmental influences should be taken into account.

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Background Posttraumatic stress disorder is characterized by an overactive noradrenergic system conferring core posttraumatic stress disorder symptoms such as hyperarousal and reexperiencing. Monoamine oxidase A is one of the key enzymes mediating the turnover of noradrenaline. Here, DNA methylation of the monoamine oxidase A gene exonI/intronI region was investigated for the first time regarding its role in posttraumatic stress disorder risk and severity. Methods Monoamine oxidase A methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells in a total sample of N=652 (441 male) patients with current posttraumatic stress disorder, patients with remitted posttraumatic stress disorder, and healthy probands (comparison group) recruited at 5 centers in Bosnia-Herzegovina, Croatia, and the Republic of Kosovo. Posttraumatic stress disorder severity was measured by means of the Clinician-Administered Posttraumatic Stress Disorder Scale and its respective subscores representing distinct symptom clusters. Results In the male, but not the female sample, patients with current posttraumatic stress disorder displayed hypermethylation of 3 CpGs (CpG3=43656362; CpG12=43656514; CpG13=43656553, GRCh38.p2 Assembly) as compared with remitted Posttraumatic Stress Disorder patients and healthy probands. Symptom severity (Clinician-Administered Posttraumatic Stress Disorder Scale scores) in male patients with current posttraumatic stress disorder significantly correlated with monoamine oxidase A methylation. This applied particularly to symptom clusters related to reexperiencing of trauma (cluster B) and hyperarousal (cluster D). Conclusions The present findings suggest monoamine oxidase A gene hypermethylation, potentially resulting in enhanced noradrenergic signalling, as a disease status and severity marker of current posttraumatic stress disorder in males. If replicated, monoamine oxidase A hypermethylation might serve as a surrogate marker of a hyperadrenergic subtype of posttraumatic stress disorder guiding personalized treatment decisions on the use of antiadrenergic agents.

Posttraumatic stress disorder can develop after individual’s exposure or witnessing of life threatening events. It is characterized by three clusters of symptoms. The course of PTSD is often chronic and impedes individual’s functioning. Studies of PTSD treatment with paroxetine provide evidence for its efficacy in reducing symptoms and its favorable profile of side-effects. The objective of this work was to determine the efficacy of paroxetine in the treatment of PTSD.The sample consisted of 30 subjects with chronic PTSD. All subjects received treatment with paroxetine in therapeutic dose range for six months. Subjects were assessed prior to therapy and following six months of treatment with paroxetine with the use of following instruments: SCL 90-R, Mississippi Questionnaire, and CGI.The results indicate statistically significant reduction on all subscales of SCL 90-R following six months of treatment, P

Objectives To identify and compare the stressors in the work environment experienced by employees in primary health care and secondary health care, amongphysiciansand nurses. Patients and methods The survey was conducted to identify types of stressors by assessing health care workers employed in the primary and secondary health care services of the Public Institution, the Health Centre of the Sarajevo Canton, using a questionnaire about stress in the workplace. Results Among all study participants stressors connected to the organization of work, finance and communication were found to affect their mental health most strongly. The results show a significant difference between primary and secondary health care in experience of stressors related to the organization of work, communication, and stressors related to the emotional and physical risks. Primary health care physicians report a significantly higher experience of stress and impact on mental health compared with other physicians related to emotional difficulties when working in the field of palliative care. Our results also indicate a significant difference between primary and secondary health providers in experiencing stressors related to the organization of work, such as: on-call duty shifts, an inadequate working environment and in the assessment of administrative work overload. Conclusion The survey identified the most intense stressors for doctors and nurses at primary and secondary levels of health care services. The results of the study indicate that doctors and nurses have a different hierarchy of stressors, as well as subjects at Primary and Secondary Health Care. The results of the study indicate that subjects et Primary Health Care perceive more stressful organizational, emotional and communicational problems.

The authors sought to describe the use of the testimony method of psychotherapy in a group of traumatized adult refugees from genocide in Bosnia-Herzegovina.The subjects were 20 Bosnian refugees in Chicago who gave written informed consent to participate in a case series study of testimony psychotherapy. All subjects received testimony psychotherapy, averaging six sessions, approximately 90 minutes, weekly or biweekly. Subjects received standardized instruments for posttraumatic stress disorder (PTSD), depression, traumatic events, global functioning, and prior psychiatric history. The instruments were administered before treatment, at the conclusion of the treatment, and at the 2- and 6-month follow-ups.The posttreatment assessments demonstrated significant decreases in the rate of PTSD diagnosis, PTSD symptom severity, and the severity of reexperiencing, avoidance, and hyperarousal symptom clusters. Depressive symptoms demonstrated a significant decrease, and there was a significant increase in scores on the Global Assessment of Functioning Scale. Two-month and 6-month follow-up assessments demonstrated further significant decreases in all symptoms and an increase in scores on the Global Assessment of Functioning Scale.This pilot study provides preliminary evidence that testimony psychotherapy may lead to improvements in PTSD and depressive symptoms, as well as to improvement of functioning, in survivors of state-sponsored violence.

Background: Quality of life assessments are increasingly present in health research. Chronic and progressive illness of a family member unavoidably affects quality of life of a family as a whole.The goals of this study were to gain insight into the family burden of chronic disorders, especially possible differences in family quality of life (FQOL) in families that have members suffering from either schizophrenia or Crohn’s disease, and families in which none of the members have chronic somatic or mental illness, as well as to pilot an instrument for this purpose. Subjects and methods: The sample consisted of 53 families with a member suffering from schizophrenia, 50 families with a member suffering from Crohn's disease, and 45 families with no identifiable chronic illnesses. An informant from each family underwent a structured face to face interview, using a questionnaire specially adapted from Family Quality of Life Survey, an instrument widely used to assess FQOL in families with members with disabilities, and which addresses nine areas of family life. Results: In the domain of health, both groups of families with chronic illnesses believe they have significantly different conditions when compared to members of the Control group. In the Crohn's disease group, families had a great deal more of challenges in accessing healthcare services; and see themselves at a disadvantage when compared to both other groups in the domain of finances. Control group offered lowest rating in the domain of support from others. Overall measures of FQOL show significant variation among the three groups, Crohn’s disease group offering lowest ratings, followed by families of mental health service users. Conclusions: Overall, FQOL seems to be lower in families that have members diagnosed with Crohn’s disease than in families with members suffering from schizophrenia. Illness-specific studies are required, as well as instruments with stronger psychometric properties and studies of determinants of FQOL. Qualitative approach should be emphasised when studying FQOL related to chronic illnesses.

To assess possible differences in quality of life assessment between the group of veterans with combat experience who meet the criteria for the diagnosis of chronic PTSD and the group of veterans with combat experience who do not meet the criteria for the diagnosis of chronic PTSD. To compare and analyze possible differences between the two groups in socio-demographic characteristics.The subjects were 100 adult men, veterans with combat exposure who met the inclusion criteria for the study and who agreed to sign the informed consent for the participations in this study. The subjects were divided in two groups (experimental group and control group), each comprising of 50 subjects. Experimental group consisted of 50 adult men, age 40-50, veterans with combat exposure who meet the criteria for the diagnosis of chronic PTSD according to ICD-10. Control group consisted of 50 adult men, age 40-50, veterans with combat exposure who do not meet the criteria for the diagnosis of chronic PTSD according to ICD-10. The subjects were assessed with the use of the following standardized psychometric instruments: MMSE, MINI, IES-90 R, MANSA; Life Stressor List and a socio-demographic questionnaire.In subjects with PTSD, assessed satisfaction with all components of the quality of life is significantly lower than in the subjects from the non-PTSD group. Yet, the scores of assessment of satisfaction with family life, although lower than in the non-PTSD group, were relatively high in the PTSD group (4.76 +/- 1.3).The results indicate the importance of factors of both PTSD diagnosis and the posttraumatic environment on the subjective perception of the quality of life for the subjects in this study.

Introduction Depressive episodes are common in bipolar illness. Treatment of bipolar depression is often problematic because standard antidepressants carry a number of disadvantages: apparent lower efficacy than in unipolar depression; risk of inducing mania; risk of inducing rapid cycling. Anticonvulsants such as carbamazepine, valproate and lamotrigine are useful in the management of bipolar disorder and they can prevent episodes of depression. There is less evidence that they have antidepressant efficacy but lamotrigine was shown to produce antidepressant effects in a placebo-controlled trial in bipolar depressed patients. Lamotrigine has a role in acute management of bipolar depression and is probably free of a risk of inducing mania or rapid cycling. Objectives To determine the efficacy of lamotrigine in treatment of patients with bipolar depression. Aims Investigation of lamotrigine efficacy with bipolar depression in 3 month-follow-up and 6 months follow-up treatment with lamotrigine. Methods The sample consisted of 30 patients with bipolar depression, age range between 26 and 58. All subjects received monotherapy with lamotrigine in the period of six months. Subjects were assessed prior to therapy and in 3 and 6 months follow-up using the following instruments: The Clinical Global Impressions scale (CGI), and Hamilton Depression Rating Scale (HAM-D-21). Results The difference between three assessments on CGI was statistically significant. The results indicate statistically significant reduction of depression on HAMD-21 following six months treatment with lamotrigine. Conclusions Lamotrigine proved to be efficient in the treatment of patients with bipolar depression for the subjects in this study.

The war in the former Yugoslavia between 1991 and 1995 destroyed the mainly hospital-based mental health care system in Bosnia and Herzegovina. This report summarizes the situation before and after the war and describes efforts to rebuild and reform mental health services under politically and economically challenging conditions. As a result of these efforts, there are now 39 multidisciplinary community mental health centers that are linked to primary care and that aim to provide prevention, treatment, and rehabilitation of mental disorders. The reform process has been supported by international initiatives and is now continuing in collaboration with other countries in South Eastern Europe.

Posttraumatic Stress Disorder (PTSD) is a major health problem in South Eastern Europe (SEE). Available treatment options are not efficient enough and the course is often chronic. Little is known about molecular mediators and moderators of pathogenesis and therapy. Genetic and epigenetic variation may be one central molecular mechanism. We therefore established a consortium combining clinical expertise on PTSD from SEE countries Bosnia-Herzegovina (Sarajevo, Tuzla and Mostar), Kosovo (Prishtina) and Croatia (Zagreb) with genetic and epigenetic competence from Germany (Würzburg) in 2011 within the framework of the DAAD (Deutscher Akademischer Austauschdienst)- funded Stability Pact for South Eastern Europe. After obtaining ethical votes and performing rater trainings as well as training in DNA extraction from EDTA blood between 2011 and 2013, we recruited 747 individuals who had experienced war- related trauma in the SEE conflicts between 1991 and 1999. 236 participants had current PTSD, 161 lifetime PTSD and 350 did not have and never had PTSD. Demographic and clinical data are currently merged together with genetic and epigenetic data in a single database to allow for a comprehensive analysis of the role of genetic and epigenetic variation in the pathogenesis and therapy of PTSD. Analyses will be done to a great degree by PhD students from participating SEE centers who in addition to participation in the project had an opportunity to take part in spring and summer schools of the DFG (Deutsche Forschungsgemeinschaft) funded Research Training Group (RTG) 1253 and thus meet PhD students from Germany and other countries We are confident that our project will not only contribute to a better understanding of genetic and epigenetic mechanisms of PTSD as a basis for future individualized and personalized therapies, but also to the academic development of South Eastern Europe.