Leveraging pleiotropy for the improved treatment of psychiatric disorders.

Over 90% of drug candidates fail in clinical trials, while it takes 10-15 years and one billion US dollars to develop a single successful drug. Drug development is more challenging for psychiatric disorders, where disease comorbidity and complex symptom profiles obscure the identification of causal mechanisms for therapeutic intervention. One promising approach for determining more suitable drug candidates in clinical trials is integrating human genetic data into the selection process. Genome-wide association studies have identified thousands of replicable risk loci for psychiatric disorders, and sophisticated statistical tools are increasingly effective at using these data to pinpoint likely causal genes. These studies have also uncovered shared or pleiotropic genetic risk factors underlying comorbid psychiatric disorders. In this article, we argue that leveraging pleiotropic effects will provide opportunities to discover novel drug targets and identify more effective treatments for psychiatric disorders by targeting a common mechanism rather than treating each disease separately.

The genetic architecture of substance use and its diverse correlations with mental health traits.

Although harmful substance use is common and represented by shared symptom features and high genetic correlations, the underlying genetic relationships between substance use traits have not been fully explored. We have investigated the genetic architecture of substance use traits through exploratory and confirmatory factor analyses using genomic structural equation modeling (Genomic SEM), and explored genetic correlations between different aspects of substance use and mental health-related traits. Genomic SEM was used to identify latent factors representing the relationships between 14 substance use traits (alcohol, nicotine, cannabis and opioid use), and to confirm or modify existing latent factors for 38 mental health-related traits. A bi-factor model best explained the genetic overlap between substance use traits, including a general substance use factor and two sub-factors representing genetic liability specific to alcohol use or smoking. The SNP-based heritability of these factors ranged from 2 to 7 % and each factor had 10 or more independent significant SNPs identified. Bivariate correlations revealed patterns of genetic overlap with other mental health-related factors unique to each substance use factor. Variations in the genetic overlap between psychiatric traits and different aspects of substance use can be used to further investigate the pleiotropy present between these traits, and explore commonalities in etiology.

Caesarean section and associated factors in Nigeria: assessing inequalities between rural and urban areas-insights from the Nigeria Demographic and Health Survey 2018.

INTRODUCTION: When medically indicated, caesarean section (CS) can be a life-saving intervention for mothers and their newborns. This study assesses the prevalence of CS and its associated factors, focussing on inequalities between rural and urban areas in Nigeria. METHODS: We disaggregated the Nigeria Demographic and Health Survey 2018 and performed analyses separately for Nigeria's overall, rural, and urban residences. We summarised data using frequency tabulations and identified factors associated with CS through multivariable logistic regression analysis. RESULTS: CS prevalence was 2.7% in Nigeria (overall), 5.2% in urban and 1.2% in rural areas. The North-West region had the lowest prevalence of 0.7%, 1.5% and 0.4% for the overall, urban and rural areas, respectively. Mothers with higher education demonstrated a greater CS prevalence of 14.0% overall, 15.3% in urban and 9.7% in rural residences. Frequent internet use increased CS prevalence nationally (14.3%) and in urban (15.1%) and rural (10.1%) residences. The southern regions showed higher CS prevalence, with the South-West leading overall (7.0%) and in rural areas (3.3%), and the South-South highest in urban areas (8.5%). Across all residences, rich wealth index, maternal age ≥ 35, lower birth order, and ≥ eight antenatal (ANC) contacts increased the odds of a CS. In rural Nigeria, husbands' education, spouses' joint healthcare decisions, birth size, and unplanned pregnancy increased CS odds. In urban Nigeria, multiple births, Christianity, frequent internet use, and ease of getting permission to visit healthcare facilities were associated with higher likelihood of CS. CONCLUSION: CS utilisation remains low in Nigeria and varies across rural-urban, regional, and socioeconomic divides. Targeted interventions are imperative for uneducated and socioeconomically disadvantaged mothers across all regions, as well as for mothers in urban areas who adhere to Islam, traditional, or 'other' religions. Comprehensive intervention measures should prioritise educational opportunities and resources, especially for rural areas, awareness campaigns on the benefits of medically indicated CS, and engagement with community and religious leaders to promote acceptance using culturally and religiously sensitive approaches. Other practical strategies include promoting optimal ANC contacts, expanding internet access and digital literacy, especially for rural women (e.g., through community Wi-Fi programs), improving healthcare infrastructure and accessibility in regions with low CS prevalence, particularly in the North-West, and implementing socioeconomic empowerment programs, especially for women in rural areas.

Meta-emotion therapy for complex trauma and binge eating: A case study.

OBJECTIVE: There is a lack of evidence guiding treatment guidelines for individuals with comorbid complex posttraumatic stress disorder (C-PTSD) and binge eating disorder (BED). The article aims to present preliminary evidence to support the proof of concept of novel therapy termed meta-emotion therapy (MET) that targeted maladaptive beliefs about emotions, for this specific comorbidity. METHOD: The single case study design involved a 35-year-old woman with a comorbid diagnosis of C-PTSD and BED, stemming from a history of childhood maltreatment, receiving 14 sessions of MET. Outcome measures related to PTSD symptoms, posttraumatic cognitions, BED cognitions and behavior, distress, and negative beliefs about emotions were assessed at initial assessment (baseline), pretreatment, posttreatment, and 1-month follow-up. RESULTS: The participant had a reliable and significant decrease in PTSD symptoms, posttraumatic cognitions, disordered eating symptoms, distress, and negative beliefs about emotions at posttreatment. Participant feedback supported the positive perception of the treatment. CONCLUSION: The findings of this study provide promising evidence to support the potential effectiveness of MET as an intervention for adults with comorbid C-PTSD and BED. Further research in the form of larger intervention trials is warranted to investigate the efficacy and long-term outcomes of MET in this population. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Challenges and considerations for treating PTSD with medicinal cannabis: the Australian clinician's perspective.

INTRODUCTION: Preclinical and experimental research have provided promising evidence that medicinal cannabis may be efficacious in the treatment of posttraumatic stress disorder (PTSD). However, implementation of medicinal cannabis into routine clinical therapies may not be straightforward. AREAS COVERED: In this review, we describe some of the clinical, practical, and safety challenges that must be addressed for cannabis-based treatment of PTSD to be feasible in a real-world setting. These issues are especially prevalent if medicinal cannabis is to be combined with trauma-focused psychotherapy. EXPERT OPINION: Future consideration of the clinical and practical considerations of cannabis use in PTSD therapy will be essential to both the efficacy and safety of the treatment protocols that are being developed. These issues include dose timing and titration, potential for addiction, product formulation, windows of intervention, and route of administration. In particular, exposure therapy for PTSD involves recall of intense emotions, and the interaction between cannabis use and reliving of trauma memories must be explored in terms of patient safety and impact on therapeutic outcomes.

Identification of drug repurposing candidates for the treatment of anxiety: A genetic approach.

Anxiety disorders are a group of prevalent and heritable neuropsychiatric diseases. We previously conducted a genome-wide association study (GWAS) which identified genomic loci associated with anxiety; however, the biological consequences underlying the genetic associations are largely unknown. Integrating GWAS and functional genomic data may improve our understanding of the genetic effects on intermediate molecular phenotypes such as gene expression. This can provide an opportunity for the discovery of drug targets for anxiety via drug repurposing. We used the GWAS summary statistics to determine putative causal genes for anxiety using MAGMA and colocalization analyses. A transcriptome-wide association study was conducted to identify genes with differential genetically regulated levels of gene expression in human brain tissue. The genes were integrated with a large drug-gene expression database (Connectivity Map), discovering compounds that are predicted to "normalise" anxiety-associated expression changes. The study identified 64 putative causal genes associated with anxiety (35 genes upregulated; 29 genes downregulated). Drug mechanisms adrenergic receptor agonists, sigma receptor agonists, and glutamate receptor agonists gene targets were enriched in anxiety-associated genetic signal and exhibited an opposing effect on the anxiety-associated gene expression signature. The significance of the project demonstrated genetic links for novel drug candidates to potentially advance anxiety therapeutics.

Management of depression in patients with coronary artery disease: A systematic review.

Depression is an independent risk factor for coronary artery disease (CAD). Both illnesses contribute significantly to the global burden of disease. This systematic literature review examines treatment interventions for CAD patients with comorbid depression. We systematically reviewed The Cochrane Library, MEDLINE, EMBASE, PsycINFO, PUBMED, CINAHL and the ISRCTN Registry for English language randomised control trials investigating treatment interventions for depression in adults with CAD and comorbid depression. Data extracted included author name(s), year published, number of participants, enrolment criteria, depression definition/measures (standardised interviews, rating scales), description of control arms and interventions (psychotherapy and/or medications), randomisation, blinding, follow-up duration, follow-up loss, depression scores and medical outcome. The database search revealed 4464 articles. The review yielded 19 trials. Antidepressant and/or psychotherapy did not significantly influence CAD outcomes in the overall population. There was no difference between antidepressant use and aerobic exercises. Psychological interventions and pharmacological interventions provide small effect on depression outcomes in CAD patients. Patient autonomy in choice of treatment is associated with greater depression treatment satisfaction, but the majority of studies are underpowered. More research is required to explore the role of neurostimulation treatment, complementary and alternative treatments.

Genetic correlation and causality assessment between post-traumatic stress disorder and coronary artery disease-related traits.

Consistent evidence from observational studies supports a risk-increasing association between post-traumatic stress disorder (PTSD) and coronary artery disease (CAD); however, the mechanisms underlying their relationship remain poorly understood. This study assesses the genetic correlation and potential causal relationship between PTSD and CAD-related traits. We analysed genome-wide associated study summary data of PTSD (cases = 23,212, controls = 151,447) with CAD-related traits (sample size up to 408,458 individuals) to achieve our study objectives. Findings revealed a significant and positive genetic correlation between PTSD and CAD (rG = 0.19, p = 3.47 × 10-2), and between PTSD and CAD traits of ischemic heart disease (genetic correlation [rG] = 0.42, p = 5.17 × 10-10), coronary arteriosclerosis (rG = 0.32, p = 3.78 × 10-7), and angina pectoris (rG = 0.48, p = 1.14 × 10-9). However, Mendelian randomisation (MR) analysis found no evidence for a significant causal association between PTSD and CAD traits, regardless of analysis direction (PTSD or CAD traits as the exposure or outcome variable). Findings from MR sensitivity analyses were consistent, suggesting that genetic liability to PTSD has no causal influence on any CAD trait and vice versa. In summary, our study provides evidence implicating a positive genetic correlation between PTSD with CAD-related traits, supporting evidence of a risk-increasing but non-causal association between them.

NLRP3 is associated with coronary artery disease in Vietnam veterans.

BACKGROUND: Previous studies have established that coronary artery disease is associated with excess inflammation. These studies have shown an elevation of both pro and anti-inflammatory cytokines in sufferers of coronary artery disease. There is increasing interest in the role played by the inflammasome Nod Like Receptor family pyrin domain containing 3 (NLRP3) in the aetiology of coronary artery disease. Increased severity of coronary artery disease correlates with higher levels of expression of NLRP3. Does NLRP3 polymorphisms play a role in the aetiology of coronary artery disease? METHOD: In a cohort of Vietnam War (n-299) veterans who have been previously exposed to trauma, NLRP3 polymorphisms were analysed for association with coronary calcium scores using analyses of variance. Independent t-test was used to analyse genotypes. In samples with a small representation of minor homozygotes, genotypes were combined and analysed using independent t-test. If any of the genotype analysis suggested the potential for a dominant or a recessive model the model was further explored. Hardy-Weinberg Equilibrium was calculated using Hardy-Weinberg equilibrium calculator including analysis for ascertainment bias. RESULTS: The NLRP3 polymorphism, rs10159239 was significantly associated (p = 0.001) with a higher raised coronary calcium score. The Single Nucleotide Polymorphism rs10159239 was examined by logistic regression with known risk factors for Coronary artery disease and remained significant (0.035). This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. CONCLUSIONS: This is the first time rs10159239 A-allele has been associated with raised coronary calcium score. Further research is needed to replicate our results in larger well-characterised cohorts.

The inflammasome NLRP12 is associated with both depression and coronary artery disease in Vietnam veterans.

Several studies have established that Major depressive disorder is associated with excess inflammation with an elevation of both pro and anti-inflammatory cytokines in major depressive disorder. In addition, individuals with major depressive disorder are at higher risk of developing coronary artery disease. The role of innate immunity and NFκB-mediated inflammation in depression and its increased association with coronary artery disease is yet to be fully elucidated. Polymorphisms in the Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat and Pyrin Domain Containing 12 (NLRP12), are associated with depression and coronary artery disease in trauma exposed individuals. In a cohort of Vietnam War veterans (n = 299) NLRP12 polymorphisms were analysed for association with depression and coronary calcium scores. The NLRP12 polymorphism, rs34436714 was associated with a higher DASS21 Score for depression (p = 0.037). NLRP12 polymorphisms rs34971363 and rs6509825 (p = 0.022 and p = 0.020) were associated with raised coronary calcium score. To our knowledge, this is the first time rs34436714 has been investigated in Vietnam veterans identifying AC as a risk genotype for depression in Caucasian cohorts. It is also the first time the rs34971363 (CG) and rs6509825 (CT) genotype have been associated with raised coronary calcium score.

The association between post-traumatic stress disorder and coronary artery disease: a meta-analysis.

OBJECTIVES: There are some psychosocial factors that have similar importance to biological factors in the genesis of coronary diseases. However, reasons for high rates of coronary heart disease in individuals with post-traumatic stress disorder (PTSD) are yet to be fully elucidated. Using a meta-analysis, we investigated the longitudinal relationship between PTSD and coronary heart disease (CHD) as an independent factor in the aetiology of CHD. METHODS: The databases of Medline, EBSCOhost and Psychoinfo were electronically searched for relevant articles. RESULTS: The pooled hazard ratio (HR) for the magnitude of the relationship between PTSD and CHD was an HR of 1.61, and p-value of p < 0.0005, 95% confidence interval (CI) [1.46-1.77] before adjustment for depression in nine studies ( N = 151,144) that met inclusion criteria. The HR estimates for the seven depression-adjusted estimates was 1.46, and a p-value of p < 0.0005, 95% CI[0.26-1.69]. CONCLUSIONS: This study demonstrates an association between CHD and PTSD.

PTSD symptoms associated with myocardial infarction: practical clinical implications.

OBJECTIVES: Several studies have demonstrated a link between post-traumatic stress disorder and myocardial infarction. We aim to determine what phenotypic features or symptom profile associated with cardiovascular disease may help with early detection and intervention. METHODS: This is a cross-sectional study. The study population comprises trauma-exposed Vietnam War veterans. RESULTS: Variables significantly associated with myocardial infarction from the bivariate analysis were avoidance memories, avoidance reminders and sleep disturbance. These variables were put into a logistic regression with known risk factors for myocardial infarction. Only sleep disturbance retained its effect, with a p-value of 0.015. CONCLUSIONS: It is concluded that sleep disturbance may be a modifiable risk factor in the treatment and prevention of myocardial infarction.

Prevalence and clinical correlates of chlamydia infection in youth who use drugs and alcohol: a good opportunity for early intervention.

AIMS: This study estimates the prevalence of chlamydia infection amongst teenage substance users aged 14-18years and investigates risk factors associated with a positive diagnosis of chlamydia infection. METHODS: Data was collected from the medical files of adolescents who attended a statewide drug and alcohol treatment facility during a three-year period commencing June 2011. RESULTS: The highest rate of chlamydia detection (18.0%) was found in the group with a reported history of abuse, a non-substance use psychiatric diagnosis, and individuals who did not complete year 10 education. CONCLUSION: Adolescents attending a detoxification facility are a suitable group for targeted chlamydia infection screening and early treatment.

Use of the urine drug screen in psychiatry emergency service.

OBJECTIVE: This study investigates if the routine use of the urine drug screen offers any diagnostic or management benefit in the assessment and treatment of psychiatry patients in a suburban psychiatry emergency service. METHODS: Data was collected retrospectively from consecutive patients 18 years and above, who presented to a large suburban hospital emergency department and had a urine drug screen ordered in the emergency department. A total of 111 patients, (with mean age of participants being 34.9 years, SD 10.2 years, minimum 18-maximum 62 years, 62.2% (69/111) were male) met the inclusion criteria. RESULTS: The most common drug group identified was benzodiazepines (59.5%; 66/111), followed by cannabis (40.5%; 45/111). Other drugs were identified at much lower levels, including amphetamines (9.0%; 10/111), opiates (4.5%; 5/111) and methadone (0%; 0/111). For most individuals only one drug was detected (55.9%; 62/111), with equal numbers (18.9%) with either zero or two drugs identified by a urine drug screen. Fewer patients had three drugs on a urine drug screen (5.4%; 6/111) or four (0.9%; 1/111). CONCLUSIONS: Qualitative urine drug screens provide limited additional information compared to history taking and has minimal impact on clinical management decisions in a psychiatry emergency service.