Rare copy number variation in posttraumatic stress disorder.

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.

Association of polygenic risk scores, traumatic life events and coping strategies with war-related PTSD diagnosis and symptom severity in the South Eastern Europe (SEE)-PTSD cohort.

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.

Fear and Depression among Residents of Bosnia and Herzegovina during COVID-19 Outbreak - Internet Survey.

BACKGROUND: Occurrence of symptoms of fear and depression among general population during the outbreak of COVID-19 seems to present an emerging problem worldwide. The aim of this study was to examine levels of fear and depressive symptoms in association with COVID-19 outbreak and to assess other contributing factors in the population of Bosnia and Herzegovina. SUBJECTS AND METHODS: Link to an anonymous questionnaire, mainly based on The Fear of COVID-19 Scale (Ahorsu et al. 2020) and two-item and nine-item Patient Health Questionnaires (PHQs) (Maurer et al. 2018) (background information, fear assessment and information regarding depression) was distributed online to general population of Bosnia and Herzegovina. RESULTS: Out of 1201 respondents, 217 (18.0%) reported experiencing fear and 341 (28.4%) reported having symptoms of depression during COVID-19 outbreak. The mean age of the subjects was 30.57±11.26. Being older (OR=1.044; 95% CI 1.031-1.057; p<0.001) and having moderate to severe depressive symptoms (OR=1.093; 95% CI 1.067-1.120; p<0.001) were independent significant predictors for developing fear; living in rural environment (OR=0.551; 95% Cl 0.325-0.935; p=0.0027) significantly decreased the risk of developing fear; being female (OR=1.750; 95% CI 1.242-2.466; p=0.001), unemployed (OR=1.557; 95% CI 1.040-2.330; p=0.032) or student (OR=1.943; 95% CI 1.450-2.604; p<0.001) were independent significant predictors for developing moderate to severe depressive symptoms in association with COVID-19. Mann Whitney U-test showed that being older was statistically associated with fear (p<0.001) and being younger was statistically associated with depressive symptoms (p<0.001). CONCLUSIONS: In conclusion, based on our findings, fear and depressive symptoms in general population of Bosnia and Herzegovina during the outbreak of COVID-19 were present in 18.06% (fear) and 28.39% (depression) of subjects and it was statistically associated with age, gender, occupation, living environment and may present a secondary uprising problem connected to outbreak of COVID-19.

Peripheral 8-iso-PGF2α as a Biomarker in Bosnian Patients with Alzheimer's Disease and Vascular Dementia.

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.

Possibilities for the future of global mental health: a scenario planning approach.

BACKGROUND: Global mental health is a widely used term describing initiatives in policies, research and practice to improve the mental health of people worldwide. It has been gaining momentum over the last 10 years, reflected in increasing funding opportunities, training programmes, and publications. In light of the rising importance of global mental health and the various uncertainties about its future directions, this paper explores what the future may hold for global mental health in 30 years' time. METHOD: A scenario planning method was used, involving a workshop with experts from four continents and a range of backgrounds, including clinical and academic psychiatry, psychology, art and music therapy, service user advisory role, funder of global health research and post-graduate students. RESULTS: Six distinct scenarios that describe potential future situations were developed: universal standards for care; worldwide coordination of research; making use of diversity; focus on social factors; globalised care through technology; mental health as a currency in global politics. CONCLUSIONS: These scenarios consider different social, economic, scientific and technological drivers and focus on distinct aspects. Some reflect a global application of possible trends in mental health, whilst others apply general global developments to mental health care. They are not fixed forecasts, but instead may help to promote discussion and debate about further developments and decisions.

Role of the Allelic Variation in the 5-Hydroxytryptamine Receptor 1A (HTR1A) and the Tryptophan Hydroxylase 2 (TPH2) Genes 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.

Association of Neuropeptide S Receptor 1 and Glutamate Decarboxylase 1 Gene Polymorphisms with Posttraumatic Stress Disorder.

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, ß=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.

Association Analysis of Maoa and Slc6a4 Gene Variation in South East European War Related Posttraumatic Stress Disorder.

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.

Genetic Susceptibility to Posttraumatic Stress Disorder: Analyses of the Oxytocin Receptor, Retinoic Acid Receptor-Related Orphan Receptor A and Cannabinoid Receptor 1 Genes.

BACKGROUND: Exposure to life-threatening events is common and everyone will most likely experience this type of trauma during their lifetime. Reactions to these events are highly heterogeneous and seems to be influenced by genes as well. Some individuals will develop posttraumatic stress disorder (PTSD), while others will not. In this study, our aim was to analyze the correlation between single nucleotide polymorphisms (SNPs) within the oxytocin receptor (OXTR) gene (rs53576 and rs2254298), the RAR-related orphan receptor A (RORA) gene (rs8042149) and the cannabinoid receptor 1 (CNR1) gene (rs1049353) and PTSD. All candidate genes have been previously associated with stress related disorders and the reaction to traumatic events. SUBJECTS AND METHODS: Participants (N=719) have been exposed to war-related trauma during the war in South-Eastern Europe (Bosnia and Herzegovina, Croatia and Kosovo). We correlated the presence and absence of current and lifetime PTSD as well as PTSD severity (Clinician Administered PTSD scale (CAPS)) and current psychopathology (Brief Symptom Inventory (BSI) score) with the mentioned SNPs. DNA was isolated from whole blood and genotyped for OXTR rs2254298 and rs53576 following previously published protocols, for RORA rs8042149 via PCR-RFLP and CNR1 rs1049353 via KASP. RESULTS: Nominally significant results were found for OXTR rs53576 in connection with the CAPS and BSI scores within lifetime PTSD patients. The additive allelic model indicated that G allele carriers achieved lower CAPS (p=0.0090) and BSI (p=0.0408) scores than participants carrying one or two copies of the A allele. These results did not withstand correction for multiple tests. No significant results were observed for OXTR rs2254298, RORA rs8042149 and CNR1 rs1049353 although the results for RORA showed a slight tendency that rs8042149 may influence the level of BSI scores in current PTSD patients. CONCLUSIONS: This study points to a role of the OXTR gene in PTSD and the related psychopathology following war related trauma.

Associations between Polymorphisms in the Solute Carrier Family 6 Member 3 and the Myelin Basic Protein Gene and Posttraumatic Stress Disorder.

BACKGROUND: Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity. SUBJECTS AND METHODS: The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection. RESULTS: No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores. CONCLUSIONS: Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.

Associations of Gene Variations in Neuropeptide Y and Brain Derived Neurotrophic Factor Genes with Posttraumatic Stress Disorder.

BACKGROUND: Individuals who are exposed to traumatic events are at an increased risk of developing posttraumatic stress disorder (PTSD), a condition during which an individual's ability to function is impaired by emotional responses to memories of those events. The gene coding for neuropeptide Y (NPY) and the gene coding for brain-derived neurotrophic factor (BDNF) are among the number of candidate gene variants that have been identified as potential contributors to PTSD. The aim of this study was to investigate the association between NPY and BDNF and PTSD in individuals who experienced war-related trauma in the South Eastern Europe (SEE) conflicts (1991-1999). SUBJECTS AND METHODS: This study included participants with current and remitted PTSD and healthy volunteers (N=719, 232 females, 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 Administered PTSD Scale (CAPS), and the Brief Symptom Inventory (BSI). DNA was isolated from whole blood and genotyped for NPY rs5574 via PCR - RFLP and NPY rs16147 and BDNF rs6265 using the KASP assay. RESULTS: Tests for deviation from Hardy-Weinberg equilibrium showed no significant results. Analyses at the categorical level yielded no associations between the affected individuals and all three SNPs when compared to controls. Within lifetime PTSD patients, the major alleles of both NPY variants showed a nominally significant association with higher CAPS scores (p=0.007 and p=0.02, respectively). Also, the major allele of rs5574C>T was associated with higher BSI scores with a nominal significance among current PTSD patients (p=0.047). The results did not withstand a Bonferroni adjustment (α=0.002). CONCLUSION: Nominally significant associations between NPY polymorphisms and PTSD susceptibility were found that did not withstand Bonferroni correction.

The Association of Catechol-O-Methyl-Transferase and Interleukin 6 Gene Polymorphisms with Posttraumatic Stress Disorder.

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 Role of TaqI DRD2 (rs1800497) and DRD4 VNTR Polymorphisms in Posttraumatic Stress Disorder (PTSD).

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.

A Candidate Gene Association Study of FKBP5 and CRHR1 Polymorphisms in Relation to War-Related Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a highly frequent and disabling psychiatric condition among war-affected populations. The FK506-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 (α=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.

Monoamine Oxidase A Gene Methylation and Its Role in Posttraumatic Stress Disorder: First Evidence from the South Eastern Europe (SEE)-PTSD Study.

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.

Relationship of Religiousness and Religious Coping with Quality of Life among War Trauma Survivors.

BACKGROUND: Long-term posttraumatic outcomes such as quality of life are dependent on a series of factors from the very exposure to traumatic events and stress appraisals, personality traits, posttraumatic growth, symptoms of Posttraumatic stress disorder (PTSD) and different coping strategies to religiousness and religious coping styles. Except of exposure to traumatic events and related stress, all other variables may have indirect mediating effects on long-term posttraumatic outcomes. The main aim of this cross-sectional study is to explore relative independent contribution of these variables in the explanation of quality of life among war trauma survivors, with a special emphasis on the variables of religiousness and religious coping. SUBJECTS AND METHODS: The research was conducted on 353 subjects who experienced war related traumatic events during the war in Bosnia and Herzegovina (B&H). The data was collected through several self-report measuring instruments: Manchester Short Assessment of Quality of Life, Stressors Check List (SCL); Religiousness Scale, Social Support Resources Scale; Religious Problem-Solving Scale, Brief RCOPE, Posttraumatic Growth Inventory and Mississippi Scale for PTSD. RESULTS: According to the results of the study, experience of loss and frequent exposure to war trauma and high levels on the primary stress appraisals, self-directing coping style and PTSD-symptoms were associated with lower perceived quality of life among the subjects. High levels of extrinsic religious orientation, effect of religiousness on social behavior, positive religious coping and posttraumatic growth were associated with higher perceived quality of life among subjects. These variables showed significant independent contribution to the prediction of the values on quality of life. CONCLUSIONS: Results of the study have a scientific significance in understanding the importance and mediating role of religiousness and religious coping for quality of life perception as one of long-term posttraumatic outcomes. Effects of religiousness on social behavior and positive religious coping showed particularly significant contribution across all prediction models for the quality of life.

Clozapine prescription rates in Southeast Europe: A cross-sectional study.

Introduction: International reports indicate that clozapine is under prescribed. Yet, this has not been explored in Southeast European (SEE) countries. This cross-sectional study investigates clozapine prescription rates in a sample of 401 outpatients with psychosis from Bosnia and Herzegovina, Kosovo by United Nations resolution, North Macedonia, Montenegro and Serbia. Methods: Descriptive analysis was used to explore clozapine prescription rates; daily antipsychotic dosage was calculated and converted into olanzapine equivalents. Patients receiving clozapine were compared to those not receiving clozapine; next those that were on clozapine monotherapy were compared to those who were on clozapine polytherapy regime. Results: It was showed that clozapine was prescribed to 37.7% of patients (with cross-country variation: from 25% in North Macedonia to 43.8% in Montenegro), with average dose of 130.7 mg/daily. The majority of patients on clozapine (70.5%) were prescribed at least one more antipsychotic (the most frequent combination was with haloperidol). Discussion: Our findings suggested that clozapine prescription rate in SEE outpatients is higher than in Western Europe. The average dose is significantly below the optimal therapeutic dosage recommended by clinical guidelines, and clozapine polytherapy is common. This might indicate that clozapine is prescribed mainly for its sedative effect rather than antipsychotic. We hope that this finding will be taken up by relevant stakeholders to address this non-evidence-based practice.

Factor structure of the brief psychiatric rating scale-expanded among outpatients with psychotic disorders in five Southeast European countries: evidence for five factors.

The Brief Psychiatric Rating Scale (BPRS) is a useful tool for measuring the severity of psychopathological symptoms among patients with psychosis. Many studies, predominantly in Western countries, have investigated its factor structure. This study has the following aims: (a) to further explore the factor structure of the BPRS-Expanded version (BPRS-E, 24 items) among outpatients with psychotic disorders in Southeast European countries; (b) to confirm the identified model; and (c) to investigate the goodness-of-fit of the three competing BPRS-E factor models derived from previous studies. The exploratory factor analysis (EFA) produced a solution with 21 items grouped into five factors, thus supporting the existence of a fifth factor, i.e., Disorganization. A follow-up confirmatory factor analysis (CFA) revealed a 19-item model (with two items removed) that fit the data well. In addition, the stability of two out of three competing factor models was confirmed. Finally, the BPRS-E model with 5 factors developed in this cross-national study was found to include a greater number of items compared to competing models.

Perceived sustainability of psychosocial treatment in low- and middle-income countries in South-Eastern Europe.

BACKGROUND: DIALOG+ is an evidence-based, generic, cost-saving and easily deliverable psychosocial intervention, adaptable to clinicians' personal manner of interaction with patients. It was implemented in mental health services in five low- and middle-income countries in South-Eastern Europe during a 12-month randomised-controlled trial (IMPULSE) to improve the effectiveness of out-patient treatment for people with psychotic disorders. AIMS: To investigate barriers and facilitators to the perceived sustainability of DIALOG+ that has been successfully implemented as a part of the IMPULSE project. METHOD: Three months after the IMPULSE trial's end, perceived sustainability of the DIALOG+ intervention was assessed via a short survey of clinicians and patients who took part in the trial. Quantitative data collected from the survey were analysed using descriptive statistics; content analysis assessed qualitative survey data. The views and experiences of key informants (patients, clinicians and healthcare policy influencers) regarding the sustainability and scale-up of DIALOG+ were further explored through semi-structured interviews. These data were explored using framework analysis. RESULTS: Clinicians mostly appreciated the comprehensiveness of DIALOG+, and patients described DIALOG+ meetings as empowering and motivating. The barrier most commonly identified by key informants was availability of financial resources; the most important facilitators were the clinically relevant structure and comprehensiveness of the DIALOG+ intervention. CONCLUSIONS: Participants showed a willingness to sustain the implementation of DIALOG+. It is important to maintain collaboration with healthcare policy influencers to improve implementation of DIALOG+ across different levels of healthcare systems and ensure availability of resources for implementing psychosocial interventions such as DIALOG+.

Maintenance Therapy of Psychosis Spectrum Disorders in a Real-World Setting: Antipsychotics Prescription Patterns and Long-Term Benzodiazepine Use.

Background: Maintenance therapy of patients with primary psychosis spectrum disorders (PSD) in the Western Balkans has received limited interest so far. The present study aimed to investigate long-term prescription patterns among outpatients with PSD. Methods: Information about prescription of antipsychotics (AP), benzodiazepines (BZD) and other psychotropic medication over a 6-month period was collected from outpatients (n = 134; ICD-10 diagnosis F20-29) recruited by a larger multi-site study, to find mean daily number of psychotropic drugs, AP prescription patterns (including AP daily dose, route of administration, monotherapy vs. polypharmacy) and BZD utilization (long-term add-on BZD therapy). Additionally, sex-differences in the variables were explored. Results: Clinically stable outpatients (age 41.7 ± 11.0; male 62.7%; duration of untreated illness 12.7 ± 8.7 years; mean number of lifetime hospitalizations 2.6 ± 0.7) were prescribed 2.8 ± 1.1 psychotropic medications daily. The mean 6-month AP dose was 14.2 ± 7.8 mg olanzapine equivalents. Long-acting injectable AP was prescribed to 25.2% of the patients. Long-term AP monotherapy was found in 52.7% patients and most of them were prescribed second generation AP (65.2%). Long-term AP polypharmacy (42.7%) was more common in males (p = 0.015). The most frequent co-prescription patterns were first generation AP plus clozapine. The highest rate of long-term AP co-prescription was found for BZD (in 42.7% cases, average 6-months daily dose of 2.8 ± 2.7 mg lorazepam equivalents) and anticholinergics (33.6%). Conclusion: Existing appropriately designed interventions aiming to safely switch the inappropriate therapeutic regimens, i.e. very high prevalence of long-term AP polypharmacy and non-rational BZD co-prescription, should be implemented in the region of Western Balkans.