Although autism has historically been conceptualized as a condition that emerges in early childhood1,2, many autistic people are diagnosed later in life3, 4–5. It is unknown whether earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Using longitudinal data from four independent birth cohorts, we demonstrate that two different socioemotional and behavioural trajectories are associated with age at diagnosis. In independent cohorts of autistic individuals, common genetic variants account for approximately 11% of the variance in age at autism diagnosis, similar to the contribution of individual sociodemographic and clinical factors, which typically explain less than 15% of this variance. We further demonstrate that the polygenic architecture of autism can be broken down into two modestly genetically correlated (rg = 0.38, s.e. = 0.07) autism polygenic factors. One of these factors is associated with earlier autism diagnosis and lower social and communication abilities in early childhood, but is only moderately genetically correlated with attention deficit–hyperactivity disorder (ADHD) and mental-health conditions. Conversely, the second factor is associated with later autism diagnosis and increased socioemotional and behavioural difficulties in adolescence, and has moderate to high positive genetic correlations with ADHD and mental-health conditions. These findings indicate that earlier- and later-diagnosed autism have different developmental trajectories and genetic profiles. Our findings have important implications for how we conceptualize autism and provide a model to explain some of the diversity found in autism. A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Patients with post-traumatic stress disorder face increased cardiovascular risk. This study examines shared genetic regions between post-traumatic stress disorder and 246 cardiovascular conditions across electronic health records, 82 cardiac imaging, and health behaviors defined by Life’s Essential 8. Post-traumatic stress disorder is genetically correlated with cardiovascular diagnoses in 33 regions, imaging traits in 4 regions, and health behaviors in 44 regions. Potentially shared causal variants between post-traumatic stress disorder and 17 cardiovascular conditions were observed in 11 regions. Subsequent observational analysis in AllofUS cohort showed post-traumatic stress disorder is associated with 13 diagnoses even after accounting for socioeconomic factors and depression. Genetically regulated proteome expression in brain and blood tissues identified 33 blood and 122 brain genes shared between the two conditions, revealing neuronal, immune, metabolic, and calcium-related mechanisms, with several genes as targets for existing drugs. These findings exhibit shared risk loci and genes are involved in tissue-specific mechanisms. Study shows PTSD predisposition shares distinct genes and genomic regions with several cardiovascular conditions. Here the findings reveal neuronal, immune, and metabolic pathways, and repurposed drug targets that further the understanding of the comorbidity.

DIALOG + is a low-cost intervention proven to improve the subjective quality of life in patients with psychosis and anxiety disorders in low- and middle-income countries. In a recent study, DIALOG + was shown to be feasible for patients in primary care settings with long-term physical conditions and to result in an improvement in patient outcomes. The aim of this qualitative study was to explore the experiences of patients and clinicians using DIALOG + in Bosnia and Herzegovina to gain a better understanding of its impact in this setting. In-depth semi-structured interviews were conducted with 11 patients and 4 physicians, as well as two focus groups with 5 patients in each, all of whom participated in the intervention. Specific life and treatment domains discussed during the sessions between patients and clinicians were also analysed to determine which domains were most frequently addressed and where patients needed the most support. The interviews were audio-recorded, transcribed, and analysed using thematic analysis. Four qualitative themes were identified: (1) DIALOG + structure and solution-oriented approach are helpful; (2) DIALOG + allows space for conversation; (3) Therapeutic relationship is improved, and (4) The intervention has its limitations. DIALOG + is a novel primary care intervention with positive effects on patients’ lives, which enhance primary care. Nevertheless, it presents a new challenge in this setting. It is necessary to make adjustments in primary care, such as providing clinicians with more extensive training and ongoing support, as well as providing more time for the intervention’s implementation. Study was registered prospectively within the ISRCTN Registry: ISRCTN17003451, 02/12/2020.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation. Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Introduction The management of long-term physical conditions is a challenge worldwide, absorbing a majority resources despite the importance of acute care. The management of these conditions is done largely in primary care and so interventions to improve primary care could have an enormous impact. However, very little data exist on how to do this. Mental distress is frequently comorbid with long term physical conditions, and can impact on health behaviour and adherence, leading to poorer outcomes. DIALOG+ is a low-cost, patient-centred and solution-focused intervention, which is used in routine patient-clinician meetings and has been shown to improve outcomes in mental health care. The question arises as to whether it could also be used in primary care to improve the quality of life and mental health of patients with long-term physical conditions. This is particularly important for low- and middle-income countries with limited health care resources. Methods An exploratory non-controlled multi-site trial was conducted in Bosnia and Herzegovina, Colombia, and Uganda. Feasibility was determined by recruitment, retention, and session completion. Patient outcomes (quality of life, anxiety and depression symptoms, objective social situation) were assessed at baseline and after three approximately monthly DIALOG+ sessions. Results A total of 117 patients were enrolled in the study, 25 in Bosnia and Herzegovina, 32 in Colombia, and 60 in Uganda. In each country, more than 75% of anticipated participants were recruited, with retention rates over 90% and completion of the intervention exceeding 92%. Patients had significantly higher quality of life and fewer anxiety and depression symptoms at post-intervention follow-up, with moderate to large effect sizes. There were no significant improvements in objective social situation. Conclusion The findings from this exploratory trial suggest that DIALOG+ is feasible in primary care settings for patients with long-term physical conditions and may substantially improve patient outcomes. Future research may test implementation and effectiveness of DIALOG+ in randomized controlled trials in wider primary care settings in low- and middle-income countries. Trial registration All studies were registered prospectively within the ISRCTN Registry. ISRCTN17003451, 02/12/2020 (Bosnia and Herzegovina), ISRCTN14018729, 01/12/2020 (Colombia) and ISRCTN50335796, 02/12/2020 (Uganda).

Posttraumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 novel). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (e.g., GRIA1, GRM8, CACNA1E), developmental, axon guidance, and transcription factors (e.g., FOXP2, EFNA5, DCC), synaptic structure and function genes (e.g., PCLO, NCAM1, PDE4B), and endocrine or immune regulators (e.g., ESR1, TRAF3, TANK). Additional top genes influence stress, immune, fear, and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation.

Objective: During the COVID-19 pandemic, fear, anxiety, and depression have become global concerns among the wider public. This study aimed to examine the occurrence of fear, anxiety and depressive symptoms associated with COVID-19, to assess influencing factors that lead to the development of these mental health conditions and to examine any changes in the mental health patterns of the society since the initial study a year ago in Sarajevo, Bosnia and Herzegovina. Method : An anonymous online survey based on Fear of COVID-19 Scale (FCV-19S), General Anxiety Disorder-7 (GAD-7) and Patients Health Questionnaires (PHQs) was conducted in the general population of Sarajevo in Bosnia and Herzegovina. Results: From 1096 subjects, 81.3% were females, 33.8% had a high school degree, 56.4% were married, 53.4% were engaged in intellectual labor, 42.3% experienced fear, 72.9% had anxiety symptoms and 70.3% had depressive symptoms during the COVID-19 pandemic and their mean age was 35.84 ± 10.86. Half (50.1%) of the subjects were COVID-19 positive and 63.8% had COVID-19 symptoms when responding to the questionnaire. Experiencing COVID-19 related fear (OR = 1.972) and having moderate to severe depressive symptoms (OR = 9.514) were associated with the development of mild to severe anxiety symptoms during the COVID-19 pandemic, which were in turn associated with the development of moderate to severe depressive symptoms (OR = 10.203) and COVID-19 related fear (OR = 2.140), respectively, thus creating a potential circulus vicious. COVID-19 positive subjects (OR = 1.454) were also more likely to develop mild to severe anxiety symptoms during the COVID-19 pandemic. Conclusion: In conclusion, the prevalence of fear, anxiety symptoms and depressive symptoms rose dramatically since the beginning of the COVID-19 pandemic in Bosnia and Herzegovina. They were interconnected and were significantly associated with age, gender, marital status and COVID-19 status. Therefore, an urgent mental health intervention is needed for the prevention of mental health problems.

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 this relationship. Methods Linkage Disequilibrium Score Regression and two-sample Mendelian randomization (MR) were used to test for genetic correlation (rg) and bidirectional causal effects using European ancestry genome-wide association studies of ADHD (20,183 cases and 35,191 controls) and six 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 rg (rg range, 0.43–0.52; P < .001). ADHD genetic liability was causally linked with increased risk for PTSD (Beta=0.367, 95% confidence interval (CI), 0.186-0.552, P=7.68x10−5). This result was not affected by heterogeneity, horizontal pleiotropy (MR Egger intercept=4.34x10−4, P=0.961), 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.

Introduction Resource-oriented interventions can be a low-cost option to improve care for patients with severe mental illnesses in low-resource settings. From 2018 to 2021 we conducted three randomized controlled trials testing resource-oriented interventions in Bosnia and Herzegovina (B&H), i.e. befriending through volunteers, multi-family groups, and improving patient-clinician meetings using the DIALOG+ intervention. All interventions were applied over 6 months and showed significant benefits for patients’ quality of life, social functioning, and symptom levels. In this study, we explore whether patient experiences point to common processes in these interventions. Methods In-depth semi-structured interviews were conducted with 15 patients from each intervention, resulting in a total sample of 45 patients. Patients were purposively selected at the end of the interventions including patients with different levels of engagement and different outcomes. Interviews explored the experiences of patients and were audio-recorded, transcribed, and analysed using the thematic analysis framework proposed by Braun and Clark. Results Three broad themes captured the overall experiences of patients receiving resource-oriented interventions: An increased confidence and agency in the treatment process; A new and unexpected experience in treatment; Concerns about the sustainability of the interventions. Conclusions The findings suggest that the three interventions – although focusing on different relationships of the patients – lead to similar beneficial experiences. In addition to being novel in the context of the mental health care system in B&H, they empower patients to take a more active and confident role in treatment. Whilst strengthening patients’ agency in their treatment may be seen as a value in itself, it may also help to achieve significantly improved treatment outcomes. This shows promise for the implementation of these interventions in other low-resource countries with similar settings.

In the original publication of the article, the initial of Professor Stefan Priebe has been incorrectly published as ‘P’ instead of’S’. The correct author name is given in this erratum.

This study aimed to analyze treatment guidelines of 12 SEE countries to identify non-pharmacological interventions recommended for schizophrenia, explore the evidence base supporting recommendations, and assess the implementation of recommended interventions. Desk and content analysis were employed to analyze the guidelines. Experts were surveyed across the 12 countries to assess availability of non-pharmacological treatments in leading mental health institutions, staff training, and inclusion in the official service price list. Most SEE countries have published treatment guidelines for schizophrenia focused on pharmacotherapy. Nine countries—Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Greece, Moldova, Montenegro, North Macedonia, and Serbia—included non-pharmacological interventions. The remaining three countries—Kosovo (UN Resolution), Romania, and Slovenia—have not published such treatment guidelines, however they are on offer in leading institutions. The median number of recommended interventions was seven (range 5–11). Family therapy and psychoeducation were recommended in most treatment guidelines. The majority of recommended interventions have a negative or mixed randomized controlled trial evidence base. A small proportion of leading mental health institutions includes these interventions in their official service price list. The interventions recommended in the treatment guidelines seem to be rarely implemented within mental health services in the SEE countries.

The assessment of negative symptoms is crucial for development of adequate therapeutic interventions. This is a challenging task due to complex clinical presentation and lack of reliable and valid instruments. This study examined the psychometric characteristics of the Clinical Assessment Interview for Negative Symptoms (CAINS). The sample consisted of 81 persons with schizophrenia or schizoaffective disorder recruited from two health institutions in the Sarajevo Canton: the Clinical Center of the University of Sarajevo and the Psychiatric Hospital of the Sarajevo Canton. The 13 CAINS items grouped into four factors (expression, motivation and satisfaction in the recreational domain, motivation and satisfaction with social relationships, motivation and satisfaction with job and education). The four-factor solution accounted for 87.83% of the variance of manifest items. The reliabilities of extracted factors were as follows: for motivation and satisfaction with social relationships α = 0.897, for motivation and satisfaction with job and education α = 0.961, for Motivation and satisfaction in the recreation domain α = 0.981, and for expression α = 0.938. The highest correlation between factors was found between Motivation and satisfaction with recreation and Motivation and satisfaction with social relationships. On the other hand, the lowest correlation was found between motivation and satisfaction with social relations and motivation and satisfaction with job and education. In conclusion, the study showed that the latent structure of CAINS is adequate, clearly interpretable, and consisted of four factors. The measure can be used for assessment of the negative symptoms in outpatients with psychosis in Bosnia and Herzegovina.

Background DIALOG+ is a patient-centred, solution-focused intervention, which aims to make routine patient-clinician meetings therapeutically effective. Existing evidence suggests that it is effective for patients with psychotic disorders in high-income countries. We tested the effectiveness of DIALOG + for patients with depressive and anxiety disorders in Bosnia and Herzegovina, a middle-income country. Methods We conducted a parallel-group, cluster randomised controlled trial of DIALOG+ in an outpatient clinic in Sarajevo. Patients inclusion criteria were: 18 years and older, a diagnosis of depressive or anxiety disorders, and low quality of life. Clinicians and their patients were randomly allocated to either the DIALOG + intervention or routine care in a 1:1 ratio. The primary outcome, quality of life, and secondary outcomes, psychiatric symptoms and objective social outcomes, were measured at 6- and 12-months by blinded assessors. Results Fifteen clinicians and 72 patients were randomised. Loss to follow-up was 12% at 6-months and 19% at 12-months. Quality of life did not significantly differ between intervention and control group after six months, but patients receiving DIALOG + had significantly better quality of life after 12 months, with a medium effect size (Cohen's d = 0.632, p = 0.007). General symptoms as well as specifically anxiety and depression symptoms were significantly lower after six and 12 months, and the objective social situation showed a statistical trend after 12 months, all in favour of the intervention group. No adverse events were reported. Limitations Delivery of the intervention was variable and COVID-19 affected 12-month follow-up assessments in both groups. Conclusion The findings suggest DIALOG + could be an effective treatment option for improving quality of life and reducing psychiatric symptoms in patients with depressive and anxiety disorders in a low-resource setting.

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.