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Introduction: Common mental disorders, such as anxiety disorders, depression, and posttraumatic stress disorder (PTSD), present a substantial health and economic burden. The gut microbiome has been associated with these psychiatric disorders via the microbiome-gut-brain axis. However, previous studies have focused on the associations between the gut microbiome and common mental disorders in European, North American and Asian populations. As part of the saNeuroGut Initiative, we assessed associations between gut microbial composition and self-reported symptoms of anxiety, depression and posttraumatic stress among South African adults., Methods: Participants completed validated, online self-report questionnaires to evaluate symptoms of state anxiety, trait anxiety, depression, and PTSD. Eighty-six stool-derived microbial DNA samples underwent sequencing of the V4 region of the 16S rRNA gene to characterise gut bacterial taxa in the sample., Results: No significant associations were observed between symptom severity scores and alpha (Shannon and Simpson indices) and beta (Aitchison distances) diversity metrics. Linear regression models revealed that the abundances of Catenibacterium, Collinsella and Holdemanella were significantly positively associated with the severity of posttraumatic stress (PTS) symptoms., Conclusion: Catenibacterium, Collinsella and Holdemanella have each previously been associated with various psychiatric disorders, with Catenibacterium having been positively associated with symptoms of PTSD in another South African cohort. This study sheds light on the relationship between the human gut microbiome and symptoms of anxiety, depression, and PTS in a South African adult sample., (The Author(s). Published by S. Karger AG, Basel.)

Background: Anxiety symptoms and poor sleep quality are common in women. The role of sex hormones, particularly progesterone, in anxiety and sleep quality in women is understudied. Measurement of hair progesterone concentrations (HPC) is a promising method to investigate the effects of progesterone on anxiety symptoms and sleep quality in women., Objectives: We analysed sociodemographic, hair-related, and clinical factors associated with HPC and investigated the association between HPC and anxiety severity and sleep quality in a sample of 159 South African women (mean age: 46.5 years; range: 18-79 years)., Methods: Data were obtained from control participants from the SHARED ROOTS study. HPC were determined using an established liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Unadjusted and adjusted multiple linear regression models were used to investigate whether sleep quality, measured with the Pittsburgh Sleep Quality Index (PSQI), and anxiety, measured with the Spielberger State-Trait Anxiety Inventory (STAI), were associated with HPC. Significant sociodemographic, hair-related, and clinical factors were adjusted for., Results: HPC was significantly associated with age, duration of sample storage, hormonal treatment, postmenopausal status, and the number of different types of trauma exposures in adjusted models. Neither anxiety severity nor sleep quality was significantly associated with HPC., Conclusions: Certain demographic, hair related, and clinical factors were associated with HPC and need to be considered in future research using HPC. Although anxiety and sleep were not associated with HPC, greater trauma exposure was associated with higher HPC, suggesting an association between severe stress and hypothalamic-pituitary-gonadal (HPG) axis functioning., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions., Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress., Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels., Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD., Competing Interests: Competing interests CYC is an employee of Biogen. NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics and Sentio Solutions for unrelated work. NRN serves as an unpaid member of the Ilumivu advisory board. SAMR receives support from the Wounded Warrior Project (WWP), Department of Veterans Affairs (VA), National Institute of Health (NIH), McCormick Foundation, Tonix Pharmaceuticals, Woodruff Foundation, and Department of Defense (DOD). Dr. Rauch receives royalties from Oxford University Press and American. KJR serves as a consultant for Acer, Bionomics, and Jazz Pharma; SABs for Sage, Boehringer Ingelheim, and Senseye. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. MBS has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Delix Therapeutics, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. MBS has stock options in Oxeia Biopharmaceuticals and EpiVario. MBS has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). MBS has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. MBS is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America.

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., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Executive function (EF) deficits are common in adults with post-traumatic stress disorder (PTSD). Macro- and micronutrient intake are potential modifiable factors that may influence EF in PTSD., Objectives: To explore the relationship between the daily dietary intake of ω-3 and ω-6 polyunsaturated fatty acids (PUFAs), vitamin C, vitamin E, vitamin D, vitamin B12 and folate, and EF in adults with PTSD., Methods: This was a cross-sectional observational study of adults with PTSD who completed neurocognitive assessments (n = 201). Digit span backwards, spatial span backwards, Stroop test and the Ruff Figural Fluency Task were used to assess EF. FoodFinder nutrient intake based on 24-h dietary recalls was used to calculate average daily nutrient intake. Multivariable linear regression models were used to regress EF on the nutrient variables., Results: Intake of vitamin E, ω-3 PUFAs, and ω-6 PUFAs were all positively associated with planning and set-shifting, with vitamin E (adjusted β = 0.20, p = 0.004) and ω-6 (adjusted β = 0.17, p = 0.01) remaining significant after adjustment for age; sex; education and body mass index. Vitamin D intake was negatively associated with interference (adjusted β = -0.21, p = 0.01). Vitamin C, vitamin B12 and folate intake were not associated with EF., Limitations: 24-h dietary recall data is limited by recall bias. Circulating nutrient levels were not measured., Conclusions: Dietary intake of vitamins E, ω-3 and ω-6 may be important modifiable factors affecting EF in adults with PTSD. Randomised controlled trials are needed to investigate whether micro- and macronutrient interventions can improve EF and other outcomes in PTSD., Competing Interests: Declaration of competing interest The views expressed in this manuscript belong to the authors and are not the official position of the institution or funder. No potential conflicts of interest were reported by the authors., (Copyright © 2024. Published by Elsevier B.V.)

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR  < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aims: Prior research, largely focused on US male veterans, indicates an increased risk of cardiovascular disease among individuals with post-traumatic stress disorder (PTSD). Data from other settings and populations are scarce. The objective of this study is to examine PTSD as a risk factor for incident major adverse cardiovascular events (MACEs) in South Africa., Methods: We analysed reimbursement claims (2011-2020) of a cohort of South African medical insurance scheme beneficiaries aged 18 years or older. We calculated adjusted hazard ratios (aHRs) for associations between PTSD and MACEs using Cox proportional hazard models and calculated the effect of PTSD on MACEs using longitudinal targeted maximum likelihood estimation., Results: We followed 1,009,113 beneficiaries over a median of 3.0 years (IQR 1.1-6.0). During follow-up, 12,662 (1.3%) persons were diagnosed with PTSD and 39,255 (3.9%) had a MACE. After adjustment for sex, HIV status, age, population group, substance use disorders, psychotic disorders, major depressive disorder, sleep disorders and the use of antipsychotic medication, PTSD was associated with a 16% increase in the risk of MACEs (aHR 1.16, 95% confidence interval (CI) 1.05-1.28). The risk ratio for the effect of PTSD on MACEs decreased from 1.59 (95% CI 1.49-1.68) after 1 year of follow-up to 1.14 (95% CI 1.11-1.16) after 8 years of follow-up., Conclusion: Our study provides empirical support for an increased risk of MACEs in males and females with PTSD from a general population sample in South Africa. These findings highlight the importance of monitoring cardiovascular risk among individuals diagnosed with PTSD.

Childhood trauma (CT) may influence brain white matter microstructure; however, few studies have examined the differential impact of distinct CT types on white matter microstructure in psychiatrically healthy adults living in a developing country. In adults without significant medical or psychiatric disorders, we investigated the association(s) between CT, including abuse and neglect, and fractional anisotropy (FA) of limbic tracts previously shown to be associated with CT. Participants underwent diffusion tensor imaging and completed the Childhood Trauma Questionnaire. Multivariate analysis of variance models were used to test the effects of total overall CT, as well as CT subtypes, on FA in six fronto-limbic tracts, adjusting for age, sex, and educational level. The final sample included 69 adults (age 47 ± 17 years; 70% female). Overall, CT had a significant main effect on FA for tracts of interest (p < .001). Greater CT severity was associated with lower FA for the bilateral and left stria terminalis (uncorrected) as well as the bilateral, left, and right anterior limb of the internal capsule (ALIC; corrected). Exposure to total non-violent/deprivational trauma specifically was associated with lower FA of the bilateral, left, and right ALIC, suggesting that distinct types of CT are associated with differential white matter changes in apparently healthy adults. The ALIC predominantly carries fibers connecting the thalamus with prefrontal cortical regions. Microstructural alterations in the ALIC may be associated with functional brain changes, which may be adaptive or increase the risk of accelerated age-related cognitive decline, maladaptive behaviors, and subsyndromal psychiatric symptoms., (© 2024 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Childhood maltreatment is associated with wide-ranging psychopathology at all stages of life. In the current study, we investigated whether posttraumatic stress disorder (PTSD) severity mediated the association between childhood maltreatment and internalizing and externalizing disorders among 262 South African trauma-exposed adolescents (aged 12-18 years). Childhood maltreatment and PTSD symptom severity were assessed using the Childhood Trauma Questionnaire and the Child PTSD Checklist, respectively. Psychiatric disorders were assessed utilizing the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime version and were grouped into internalizing or externalizing disorders. Hierarchal logistic regression was used to assess the association of childhood maltreatment subtype with internalizing and externalizing disorders, controlling for age and gender, with PTSD symptom severity added to the final model. We found that sexual abuse was significantly associated with internalizing disorders, although this effect was no longer significant when PTSD was added to the model demonstrating that PTSD mediated the association between sexual abuse and internalizing disorders. Physical abuse, but not PTSD, was associated with externalizing disorders. Physical abuse, emotional neglect, and PTSD were associated with comorbid internalizing and externalizing disorders. These findings have implications for intervention and prevention strategies targeted at trauma-exposed adolescents with a history of childhood maltreatment.

Background: Although literature globally indicates varied neurological and/or neuropsychiatric manifestations (NNM) and complications associated with coronavirus disease 2019 (COVID-19), information about NNM in infected hospitalised patients on the African continent remains limited., Aim: To describe the presentation of NNM and compare patients with and without NNM considering demographic and clinical profiles, treatment, and outcomes., Setting: Tygerberg Hospital, Cape Town, South Africa., Methods: Retrospective medical record review of the first 100 consecutively admitted COVID-19 patients (64 females, mean age 47.6 years) between March and June 2020., Results: Of the 98 patients included in the analysis, 56.1% had at least one NNM. The most common NNM were myalgia (32.7%), headache (21.4%), loss of smell and/or taste (15.3%), and delirium (10.2%). Patients with and without NNM did not differ with respect to demographic characteristics. Patients with NNM had significantly more constitutional symptoms ( p = 0.017) and were more likely to have neurological and/or neuropsychiatric comorbid conditions (10.9% vs. 0.0%, p = 0.033) than those without NNM. Patients without documented NNM were more likely to have abnormalities on chest X-ray ( p = 0.009) than those with NNM. Coronavirus disease 2019 related treatment and mortality did not differ between the groups., Conclusion: Neurological and/or neuropsychiatric manifestations were common in hospitalised patients with COVID-19. The results suggest that while COVID-19 patients with NNM may have less of a respiratory phenotype they nonetheless have equivalent mortality rates., Contribution: This study highlights the common NNM in patients with COVID-19 admitted to Tygerberg Hospital early in the pandemic and adds to the growing evidence of COVID-19 NNM., Competing Interests: The authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article., (© 2023. The Authors.)

COVID-19 affected the well-being of healthcare workers (HCWs) globally. Mental health app interventions (MHAIs) may offer appropriate and accessible means to support HCWs' mental health. We conducted a pilot randomised controlled crossover trial involving 34 clinicians randomised to either a MHAI or a waitlisted group. After one month, outcome assessments were repeated and the waitlisted group then crossed over to the MHAI; they again completed outcome assessments after a month. The primary outcomes were feasibility, assessed with the Systems Usability Scale (SUS), and acceptability, assessed with the Client Satisfaction Questionnaire (CSQ). Secondary outcomes included efficacy for various mental health parameters. The SUS and CSQ scores indicated above average feasibility and acceptability. There was a significant difference in anxiety from baseline to 1-month follow-up between the groups, with greater improvement in the MHAI group. The groups differed in resilience and patient-related burnout from baseline to 1-month follow-up, with a trend towards significance, with greater improvements in the MHAI group. Anxiety and acute stress disorder severity improved significantly from pre- to post-intervention. We demonstrated that MHAIs hold potential for improving well-being of HCWs, although these findings will need to be replicated in adequately powered trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

In this narrative review, we examine the association between gut dysbiosis, neuroinflammation, and stress-linked disorders, including depression, anxiety, and post-traumatic stress disorder (PTSD), and investigate whether tryptophan (TRP) metabolism and platelets play a role in this association. The mechanisms underlying the aetiology of stress-linked disorders are complex and not yet completely understood. However, a potential link between chronic inflammation and these disorders may potentially be found in TRP metabolism and platelets. By critically analysing existing literature on platelets, the gut microbiome, and stress-linked disorders, we hope to elicit the role of platelets in mediating the effects on serotonin (5-HT) levels and neuroinflammation. We have included studies specifically investigating platelets and TRP metabolism in relation to inflammation, neuroinflammation and neuropsychiatric disorders. Alteration in microbial composition due to stress could contribute to increased intestinal permeability, facilitating the translocation of microbial products, and triggering the release of pro-inflammatory cytokines. This causes platelets to become hyperactive and secrete 5-HT into the plasma. Increased levels of pro-inflammatory cytokines may also lead to increased permeability of the blood-brain barrier (BBB), allowing inflammatory mediators entry into the brain, affecting the balance of TRP metabolism products, such as 5-HT, kynurenic acid (KYNA), and quinolinic acid (QUIN). These alterations may contribute to neuroinflammation and possible neurological damage. Furthermore, platelets can cross the compromised BBB and interact with astrocytes and neurons, leading to the secretion of 5-HT and pro-inflammatory factors, exacerbating inflammatory conditions in the brain. The mechanisms underlying neuroinflammation resulting from peripheral inflammation are still unclear, but the connection between the brain and gut through the bloodstream could be significant. Identifying peripheral biomarkers and mechanisms in the plasma that reflect neuroinflammation may be important. This review serves as a foundation for further research on the association between the gut microbiome, blood microbiome, and neuropsychiatric disorders. The integration of these findings with protein and metabolite markers in the blood may expand our understanding of the subject., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic systemic inflammation has been implicated in trauma exposure, independent of a psychiatric diagnosis, and in posttraumatic stress disorder (PTSD) and its highly comorbid conditions, such as metabolic syndrome (MetS). The present study used network analysis to examine the interacting associations between pro-inflammatory cytokines, posttraumatic stress (PTS) symptoms and symptom clusters, and individual components of MetS, in a cohort of 312 participants (n = 139 PTSD cases, n = 173 trauma-exposed controls). Pro-inflammatory cytokines were measured in serum samples using immunoturbidimetric and multiplex assays. Three network models were assessed, and the decision on which model to use was guided by network stability estimates and denseness. Weak negative associations were observed between interleukin one beta (IL-1β) and detachment (D6) and irritability (E1); tumour necrosis factor alpha (TNFα) and hypervigilance (E3); and C-reactive protein (CRP) and emotional cue reactivity (B4), which could be due to high cortisol levels present in a female-majority cohort. Network models also identified positive associations between CRP and waist circumference, blood pressure, and high-density lipoprotein cholesterol (HDL-C). The strongest association was observed between CRP and waist circumference, providing evidence that central obesity is an important inflammatory component of MetS. Some networks displayed high instability, which could be due to the small pool of participants with viable cytokine data. Overall, this study provides evidence for associations between inflammation, PTS symptoms and components of MetS. Future longitudinal studies measuring pro-inflammatory cytokines in the immediate aftermath of trauma are required to gain better insight into the role of inflammation in trauma-exposure and PTSD., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The molecular mechanisms underlying posttraumatic stress disorder (PTSD) are yet to be fully elucidated, especially in underrepresented population groups. Expression quantitative trait loci (eQTLs) are DNA sequence variants that influence gene expression, in a local (cis-) or distal (trans-) manner, and subsequently impact cellular, tissue, and system physiology. This study aims to identify genetic loci associated with gene expression changes in a South African PTSD cohort. Genome-wide genotype and RNA-sequencing data were obtained from 32 trauma-exposed controls and 35 PTSD cases of mixed-ancestry, as part of the SHARED ROOTS project. The first approach utilised 108 937 single-nucleotide polymorphisms (SNPs) (MAF > 10%) and 11 312 genes with Matrix eQTL to map potential eQTLs, while controlling for covariates as appropriate. The second analysis was focused on 5638 SNPs related to a previously calculated PTSD polygenic risk score for this cohort. SNP-gene pairs were considered eQTLs if they surpassed Bonferroni correction and had a false discovery rate <0.05. We did not identify eQTLs that significantly influenced gene expression in a PTSD-dependent manner. However, several known cis-eQTLs, independent of PTSD diagnosis, were observed. rs8521 (C > T) was associated with TAGLN and SIDT2 expression, and rs11085906 (C > T) was associated with ZNF333 expression. This exploratory study provides insight into the molecular mechanisms associated with PTSD in a non-European, admixed sample population. This study was limited by the cross-sectional design and insufficient statistical power. Overall, this study should encourage further multi-omics approaches towards investigating PTSD in diverse populations., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

The intersecting epidemics of HIV and hazardous or harmful alcohol use (HAU) can have significant detrimental consequences. Both HIV and HAU have independent negative influences on executive function. Dysfunction in reward processing may play a role in these co-occurring epidemics. In this cross-sectional case-control study, we investigated the association of HAU with reward processing amongst people with HIV (PWH). We investigated the function of the ventral-striatal reward system using a functional MRI (fMRI) monetary incentive delay (MID) task in a sample of 60 South African adults (mean age 32.7 years): 42 living with HIV and on ART (21 with harmful alcohol use [HIV + HAU], 21 without [HIV-HAU]) and 18 healthy controls, matched for age, gender, and resident community. Education significantly influenced task performance, with those with a secondary level of education demonstrating a greater increase in reaction time (p = 0.048) and accuracy (p = 0.002) than those without. There were no significant differences in reward anticipation in the ventral striatum (VS) between HIV + HAU, HIV-HAU, and healthy controls when controlling for level of education. There were also no significant differences in reward outcome in the orbitofrontal cortex (OFC) between HIV + HAU, HIV-HAU, and healthy controls when controlling for level of education. In a sample of South African adults, we did not demonstrate significant differences in reward anticipation in the VS and reward outcome in the OFC in PWH, with and without HAU, and controls. Factors, such as task performance, education, and depression may have influenced our results. Further studies are needed to better delineate the potential links between HIV, HAU, and depression and reward system function., (© 2022. Journal of NeuroVirology, Inc.)

Introduction: There has been a sharp increase in the use of digital health interventions in global health, particularly mobile health applications, in recent years. The extreme shortage of health care providers trained in mental health screening and intervention in low- and middle-income countries raises questions about the applicability of mobile applications to deliver these services due to their accessibility and availability. This exploratory paper describes the development and feasibility assessment of a mobile screening application for the detection of mental disorders among adolescents in Zambia and South Africa. Methods : Eighty-two health care workers (HCW) working in primary care evaluated the acceptability and practicality of the mobile screening application after receiving brief training. The evaluation included questions from the Mobile Application Rating Scale (MARS) as well as open-ended questions. Results : The acceptability of the screening app was high and study participants were positive about using the app in routine care. Problems with internet connectivity, and time and staff constraints were perceived as the main barriers to regular use. Conclusion : HCW in primary care were able and willing to use a mobile screening app for the detection of mental health problems among treatment-seeking adolescents. Implementation in clinical practice needs to be further evaluated.

Background: Childhood maltreatment leads to lifelong health risks, particularly in women. Although reproductive health has been linked to such maltreatment, limited literature exists on its association with polycystic ovary syndrome (PCOS)., Objectives: In a sample of psychiatrically healthy women, we evaluated the impact of child maltreatment (subtypes of abuse and neglect) on women's reproductive health outcomes, specifically PCOS., Participants and Setting: The 237 psychiatrically healthy women, aged between 18 and 79 years, were control participants in a case-control study (SHARED ROOTS), conducted in Cape Town, South Africa, between May 2014 and June 2017., Methods: Probable PCOS was based on a history of symptoms of ovulatory dysfunction and hyperandrogenism or a diagnosis of PCOS. We conducted hierarchical logistic regression models to assess which child maltreatment subtypes (emotional, physical and sexual abuse and emotional and physical neglect) were significantly associated with PCOS, controlling for sociodemographic and clinical factors., Results: Probable PCOS was present in 29 (12.2 %) women. Emotional abuse (31.6 %) was the most frequent type of child maltreatment and was significantly associated with PCOS (OR = 5.11, CI 1.87; 13.98), including when other maltreatment types were accounted for (OR = 3.90, CI 1.27; 12.02). Physical abuse was associated with PCOS (OR = 4.21, CI 1.43; 12.38), but was not significant when other maltreatment types were factored in., Conclusions: Child maltreatment is independently associated with PCOS in women without psychiatric disorders. In the context of all maltreatment subtypes, emotional abuse remained associated with PCOS, suggesting its unique effect on this endocrinopathy., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: Individuals with schizophrenia demonstrate higher rates of metabolic syndrome (MetS) than the general population. Hair cortisol concentrations (HCC) reflect longer-term cortisol secretion and can provide additional insights into the role of the hypothalamic pituitary adrenal (HPA) axis in schizophrenia and co-occurring MetS., Methods: In a case-control study of 16 patients with schizophrenia (11 first episode psychosis [FEP] and 5 chronic) and 21 controls hair samples, representing a 3-month retrospective window of cortisol, were collected and analysed utilizing liquid chromatography tandem mass spectrometry. We investigated whether schizophrenia and MetS co-occurrence were associated with HCC utilizing multivariate regression models. We also explored the longitudinal trajectory of HCC in FEP patients by conducting a mixed models analysis., Results: At baseline HCC were significantly lower (Cohen's d = 0.88) in patients with schizophrenia than in controls (p = .014). HCC increased from baseline to month-12 in FEP patients compared to controls, demonstrating a trend towards significance (p = .097). MetS was not associated with HCC at baseline, but HCC increased significantly from baseline to month-12 in relation to MetS (p = .037)., Conclusions: In a subgroup of schizophrenia patients, psychosis may be associated with a blunted HPA axis with lower long-term cortisol output. MetS was associated with an increase in HCC and elevated cortisol levels observed in schizophrenia may be related to increased rates of MetS in schizophrenia patients., (© 2022 John Wiley & Sons Australia, Ltd.)

Objective: Several studies suggest a relationship between atopy and psychiatric disorders, but few have investigated the association between atopic conditions and posttraumatic stress disorder (PTSD). We sought to compare the rates of atopy and allergies in a South African case-control study of 220 patients with PTSD (mean age 41.7 years, SD = 11.7) and 196 trauma exposed controls (TEC, mean age 45.4 years, SD = 14.7) conducted in Cape Town, South Africa from May 2014 to June 2017., Methods: Self-reported atopic conditions and allergies were regressed on PTSD, as determined with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), in multivariate logistic regression models, controlling for age, gender, body mass index, physical activity, lifetime and childhood trauma, and time since index trauma., Results: Rates of lifetime atopy (p = 0.03), current asthma (p = 0.04), lifetime allergic rhinitis (p = 0.002), and current allergic rhinitis (p = 0.004) were significantly higher in patients than TEC on bivariate analysis. On multivariate analysis, rates of current atopy (Cohen's d = 0.26, p = 0.04) and current allergic rhinitis (Cohen's d = 0.34, p = 0.012) were significantly higher in patients with PTSD than in TEC. Current eczema (p = 0.24), current asthma (p = 0.26), and allergies (p = 0.59) were not associated with PTSD., Conclusions: Rates of atopy are higher in participants with PTSD than TEC, and this effect is related to higher rates of allergic rhinitis. Further studies are needed to elucidate the pathways linking allergic rhinitis and PTSD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Posttraumatic stress disorder (PTSD) can be a chronic and disabling condition. Post-traumatic nightmares (PTNs) form a core component of PTSD and are highly prevalent in this patient population. Nightmares in PTSD have been associated with significant distress, functional impairment, poor health outcomes, and decreased quality of life. Nightmares in PTSD are also an independent risk factor for suicide. Nightmare cessation can lead to improved quality of life, fewer hospital admissions, lower healthcare costs, and reduced all-cause mortality. Effective treatment of nightmares is critical and often leads to improvement of other PTSD symptomatology. However, approved pharmacological agents for the treatment of PTSD have modest effects on sleep and nightmares, and may cause adverse effects. No pharmacological agent has been approved specifically for the treatment of PTNs, but multiple agents have been studied. This current narrative review aimed to critically appraise proven as well as novel pharmacological agents used in the treatment of PTNs. Evidence of varying quality exists for the use of prazosin, doxazosin, clonidine, tricyclic antidepressants, trazodone, mirtazapine, atypical antipsychotics (especially risperidone, olanzapine and quetiapine), gabapentin, topiramate, and cyproheptadine. Evidence does not support the use of venlafaxine, β-blockers, benzodiazepines, or sedative hypnotics. Novel agents such as ramelteon, cannabinoids, ketamine, psychedelic agents, and trihexyphenidyl have shown promising results. Large randomized controlled trials (RCTs) are needed to evaluate the use of these novel agents. Future research directions are identified to optimize the treatment of nightmares in patients with PTSD., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The association between childhood trauma exposure and risk of developing psychopathology may in part be mediated by the effects of chronic stress on dopaminergic neurotransmission. However, little is known about the differential effects of distinct trauma types on reward processing, particularly in adults without concurrent medical or psychiatric disorders. We examined the association of childhood trauma exposure, including the differential effects of abuse and neglect, with reward processing in healthy adults (n = 114). Functional magnetic resonance imaging during a monetary incentive delay task was used to assess neural activity in the ventral striatum and orbitofrontal cortex in relation to reward anticipation and reward outcome, respectively. Exposure to childhood trauma, including abuse and neglect, was assessed using the Childhood Trauma Questionnaire-Short Form. We found a significant effect for abuse on ventral striatal activation during reward anticipation, adjusting for age, sex, scanner site, educational level, and household monthly income. There were no effects for abuse or neglect, independently or combined, on orbitofrontal cortex activation during reward outcome. Our findings suggest differential effects of childhood abuse on ventral striatum activation during reward anticipation in healthy adults., (© 2022 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Aims: The coronavirus disease 2019 (COVID-19) pandemic and ensuing restrictions have negatively affected the mental health and well-being of the general population, and there is increasing evidence suggesting that lockdowns have led to a disruption of health services. In March 2020, South Africa introduced a lockdown in response to the COVID-19 pandemic, entailing the suspension of all non-essential activities and a complete ban of tobacco and alcohol sales. We studied the effect of the lockdown on mental health care utilisation rates in private-sector care in South Africa., Methods: We conducted an interrupted time-series analysis using insurance claims from 1 January 2017 to 1 June 2020 of beneficiaries 18 years or older from a large private sector medical insurance scheme. We calculated weekly outpatient consultation and hospital admission rates for organic mental disorders, substance use disorders, serious mental disorders, depression, anxiety, other mental disorders, any mental disorder and alcohol withdrawal syndrome. We calculated adjusted odds ratios (OR) for the effect of the lockdown on weekly outpatient consultation and hospital admission rates and the weekly change in rates during the lockdown until 1 June 2020., Results: 710 367 persons were followed up for a median of 153 weeks. Hospital admission rates (OR 0.38; 95% confidence interval (CI) 0.33-0.44) and outpatient consultation rates (OR 0.74; 95% CI 0.63-0.87) for any mental disorder decreased substantially after the introduction of the lockdown and did not recover to pre-lockdown levels by 1 June 2020. Health care utilisation rates for alcohol withdrawal syndrome doubled after the introduction of the lockdown, but the statistical uncertainty around the estimates was large (OR 2.24; 95% CI 0.69-7.24)., Conclusions: Mental health care utilisation rates for inpatient and outpatient services decreased substantially after the introduction of the lockdown. Hospital admissions and outpatient consultations for alcohol withdrawal syndrome increased after the introduction of the lockdown, but statistical uncertainty precludes strong conclusions about a potential unintended effect of the alcohol sales ban. Governments should integrate strategies for ensuring access and continuity of essential mental health services during lockdowns in pandemic preparedness planning.

Childhood trauma (CT) is well established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high-density lipoprotein and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro-inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental influences provide a means whereby the effects of CT can be biologically embedded and persist into adulthood to affect health and well-being. The methylome regulates the transcription of genes involved in the stress response, metabolism and inflammation. This narrative review examines the evidence for DNA methylation in CT and MetS in order to identify shared neuroendocrine and immune correlates that may mediate the increased risk of MetS following CT exposure. Our review specifically highlights differential methylation of FKBP5, the gene that encodes FK506-binding protein 51 and has pleiotropic effects on stress responding, inflammation and energy metabolism, as a central candidate to understand the molecular aetiology underlying CT-associated MetS risk., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

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., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Evidence suggests that shared pathophysiological mechanisms in neuropsychiatric disorders (NPDs) may contribute to risk and resilience. We used single-gene and network-level transcriptomic approaches to investigate shared and disorder-specific processes underlying posttraumatic stress disorder (PTSD), Parkinson's disease (PD) and schizophrenia in a South African sample. RNA-seq was performed on blood obtained from cases and controls from each cohort. Gene expression and weighted gene correlation network analyses (WGCNA) were performed using DESeq2 and CEMiTool, respectively. Significant differences in gene expression were limited to the PTSD cohort. However, WGCNA implicated, amongst others, ribosomal expression, inflammation and ubiquitination as key players in the NPDs under investigation. Differential expression in ribosomal-related pathways was observed in the PTSD and PD cohorts, and focal adhesion and extracellular matrix pathways were implicated in PD and schizophrenia. We propose that, despite different phenotypic presentations, core transdiagnostic mechanisms may play important roles in the molecular aetiology of NPDs., (© 2022. The Author(s).)

Posttraumatic stress disorder (PTSD) imposes a significant burden on patients and communities. Although the microbiome-gut-brain axis has been proposed as a mediator or moderator of PTSD risk and persistence of symptoms, clinical data directly delineating the gut microbiome's relationship to PTSD are sparse. This study investigated associations between the gut microbiome and mental health outcomes in participants with PTSD (n = 79) and trauma-exposed controls (TECs) (n = 58). Diagnoses of PTSD, major depressive disorder (MDD), and childhood trauma were made using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), MINI International Neuropsychiatric Interview (MINI), and Childhood Trauma Questionnaire (CTQ), respectively. Microbial communities from stool samples were profiled using 16S ribosomal RNA gene V4 amplicon sequencing and tested for associations with PTSD-related variables of interest. Random forest models identified a consortium of four genera, i.e.,  a combination of Mitsuokella, Odoribacter, Catenibacterium, and Olsenella, previously associated with periodontal disease, that could distinguish PTSD status with 66.4% accuracy. The relative abundance of this consortium was higher in the PTSD group and correlated positively with CAPS-5 and CTQ scores. MDD diagnosis was also associated with increased relative abundance of the Bacteroidetes phylum. Current use of psychotropics significantly impacted community composition and the relative abundances of several taxa. Early life trauma may prime the microbiome for changes in composition that facilitate a pro-inflammatory cascade and increase the risk of development of PTSD. Future studies should rigorously stratify participants into healthy controls, TECs, and PTSD (stratified by psychotropic drug use) to explore the role of the oral-gut-microbiome-brain axis in trauma-related disorders., Competing Interests: Declaration of Competing Interest CAL. serves on the Scientific Advisory Board of Immodulon Therapeutics, Ltd., is Cofounder and Chief Scientific Officer of Mycobacteria Therapeutics Corporation, and is a member of the faculty of the Integrative Psychiatry Institute, Boulder, Colorado. The remaining authors have no competing interests to disclose., (Copyright © 2021 Elsevier B.V. and ECNP. All rights reserved.)

Glucocorticoids and inflammatory markers can influence cognitive function. Hair cortisol concentrations (HCC) reflect longer-term hypothalamic pituitary adrenal (HPA) axis function and combined with immune markers can provide insights into how HPA-axis and immune pathways interact to influence cognition. We examined the association between HCC and high sensitivity c-reactive protein (hsCRP) levels, as well as the interaction between HCC and hsCRP, and cognitive function in a sample of 153 females, aged between 18 and 79 years, from a cross-sectional case-control study (SHARED ROOTS), conducted in Cape Town, South Africa from May 2014 until June 2017. We examined whether HCC and hsCRP levels were associated with performance on neurocognitive tests in both unadjusted and adjusted linear regression models. HCC demonstrated a significant inverse association with verbal working memory in both unadjusted (p = 0.010) and adjusted (p = 0.016) analyses. There were significant interactions between HCC and hsCRP on verbal intelligence (p = 0.016), language (p = 0.023) and executive function (p = 0.008) scores, such that at low HCC hsCRP levels were positively associated with language (p = 0.020) and executive function (p = 0.006) scores and at high HCC hsCRP levels were inversely associated with verbal intelligence (p = 0.034) scores. Though the results did not survive correction for multiple comparisons, they suggest stress-related neuroendocrine effects on working memory impairment. Furthermore, under physiological conditions and low long-term HCC, there may be positive effects of peripheral inflammatory markers on cognitive performance, whereas there may be detrimental effects when the HPA-axis is dysregulated as reflected by high long-term cortisol output., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Growing research suggests that posttraumatic stress disorder (PTSD) may be a risk factor for poor cardiovascular health, and yet our understanding of who might be at greatest risk of adverse cardiovascular outcomes after trauma is limited. In this study, we conducted the first examination of the individual and synergistic contributions of PTSD symptoms and blood pressure genetics to continuous blood pressure levels. We harnessed the power of the Psychiatric Genomics Consortium-PTSD Physical Health Working Group and investigated these associations across 11 studies of 72,224 trauma-exposed individuals of European ( n = 70,870) and African ( n = 1,354) ancestry. Genetic contributions to blood pressure were modeled via polygenic scores (PGS) for systolic blood pressure (SBP) and diastolic blood pressure (DBP) that were derived from a prior trans-ethnic blood pressure genome-wide association study (GWAS). Results of trans-ethnic meta-analyses revealed significant main effects of the PGS on blood pressure levels [SBP: β = 2.83, standard error (SE) = 0.06, p < 1E-20; DBP: β = 1.32, SE = 0.04, p < 1E-20]. Significant main effects of PTSD symptoms were also detected for SBP and DBP in trans-ethnic meta-analyses, though there was significant heterogeneity in these results. When including data from the largest contributing study - United Kingdom Biobank - PTSD symptoms were negatively associated with SBP levels (β = -1.46, SE = 0.44, p = 9.8E-4) and positively associated with DBP levels (β = 0.70, SE = 0.26, p = 8.1E-3). However, when excluding the United Kingdom Biobank cohort in trans-ethnic meta-analyses, there was a nominally significant positive association between PTSD symptoms and SBP levels (β = 2.81, SE = 1.13, p = 0.01); no significant association was observed for DBP (β = 0.43, SE = 0.78, p = 0.58). Blood pressure PGS did not significantly moderate the associations between PTSD symptoms and blood pressure levels in meta-analyses. Additional research is needed to better understand the extent to which PTSD is associated with high blood pressure and how genetic as well as contextual factors may play a role in influencing cardiovascular risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sumner, Maihofer, Michopoulos, Rothbaum, Almli, Andreassen, Ashley-Koch, Baker, Beckham, Bradley, Breen, Coleman, Dale, Dennis, Feeny, Franz, Garrett, Gillespie, Guffanti, Hauser, Hemmings, Jovanovic, Kimbrel, Kremen, Lawford, Logue, Lori, Lyons, Maples-Keller, Mavissakalian, McGlinchey, Mehta, Mellor, Milberg, Miller, Morris, Panizzon, Ressler, Risbrough, Rothbaum, Roy-Byrne, Seedat, Smith, Stevens, van den Heuvel, Voisey, Young, Zoellner, PGC-PTSD Physical Health Working Group, Nievergelt and Wolf.)

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants ( n = 260) and controls ( n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD ( p < 5 × 10 -6 ). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke's pseudo R 2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score ( R 2 = 0.00856, p = 0.0367) and PCL-5 score ( R 2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke's pseudo R 2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2 , corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Swart, van den Heuvel, Lewis, Seedat and Hemmings.)

Aims: Mental disorders are common in people living with HIV (PLWH) but often remain untreated. This study aimed to explore the treatment gap for mental disorders in adults followed-up in antiretroviral therapy (ART) programmes in South Africa and disparities between ART programmes regarding the provision of mental health services., Methods: We conducted a cohort study using ART programme data and linked pharmacy and hospitalisation data to examine the 12-month prevalence of treatment for mental disorders and factors associated with the rate of treatment for mental disorders among adults, aged 15-49 years, followed-up from 1 January 2012 to 31 December 2017 at one private care, one public tertiary care and two pubic primary care ART programmes in South Africa. We calculated the treatment gap for mental disorders as the discrepancy between the 12-month prevalence of mental disorders in PLWH (aged 15-49 years) in South Africa (estimated based on data from the Global Burden of Disease study) and the 12-month prevalence of treatment for mental disorders in ART programmes. We calculated adjusted rate ratios (aRRs) for factors associated with the treatment rate of mental disorders using Poisson regression., Results: In total, 182 285 ART patients were followed-up over 405 153 person-years. In 2017, the estimated treatment gap for mental disorders was 40.5% (95% confidence interval [CI] 19.5-52.9) for patients followed-up in private care, 96.5% (95% CI 95.0-97.5) for patients followed-up in public primary care and 65.0% (95% CI 36.5-85.1) for patients followed-up in public tertiary care ART programmes. Rates of treatment with antidepressants, anxiolytics and antipsychotics were 17 (aRR 0.06, 95% CI 0.06-0.07), 50 (aRR 0.02, 95% CI 0.01-0.03) and 2.6 (aRR 0.39, 95% CI 0.35-0.43) times lower in public primary care programmes than in the private sector programmes., Conclusions: There is a large treatment gap for mental disorders in PLWH in South Africa and substantial disparities in access to mental health services between patients receiving ART in the public vs the private sector. In the public sector and especially in public primary care, PLWH with common mental disorders remain mostly untreated.

Background and Purpose: Most research regarding child and adolescent mental health prevention and promotion in low-and middle-income countries is undertaken in high-income countries. This systematic review set out to synthesise findings from epidemiological studies, published between 2008 and 2020, documenting the prevalence of mental health problems in adolescents from across sub-Saharan Africa., Methods: A systematic search of multiple databases (MEDLINE, PsycINFO, Scopus) and Google Scholar was conducted guided by the Joanna Briggs Institute (JBI) Reviewer's manual for systematic reviews of observational epidemiological studies. Studies included reported prevalence outcomes for adolescents aged 10-19 using either clinical interviews or standardized questionnaires to assess psychopathology. Clinical samples were excluded., Results: The search yielded 1 549 records of which 316 studies were assessed for eligibility and 51 met the inclusion criteria. We present a qualitative synthesis of 37 of these 51 included articles. The other 14 studies reporting prevalence rates for adolescents living with HIV are published elsewhere. The prevalence of depression, anxiety disorders, emotional and behavioural difficulties, posttraumatic stress and suicidal behaviour in the general adolescent population and selected at-risk groups in 16 sub-Saharan countries (with a total population of 97 616 adolescents) are reported., Competing Interests: The authors have declared that no competing interests exist.

Despite the progress made in HIV treatment and prevention, HIV remains a major cause of adolescent morbidity and mortality in sub-Saharan Africa. As perinatally infected children increasingly survive into adulthood, the quality of life and mental health of this population has increased in importance. This review provides a synthesis of the prevalence of mental health problems in this population and explores associated factors. A systematic database search (Medline, PsycINFO, Scopus) with an additional hand search was conducted. Peer-reviewed studies on adolescents (aged 10-19), published between 2008 and 2019, assessing mental health symptoms or psychiatric disorders, either by standardized questionnaires or by diagnostic interviews, were included. The search identified 1461 articles, of which 301 were eligible for full-text analysis. Fourteen of these, concerning HIV-positive adolescents, met the inclusion criteria and were critically appraised. Mental health problems were highly prevalent among this group, with around 25% scoring positive for any psychiatric disorder and 30-50% showing emotional or behavioral difficulties or significant psychological distress. Associated factors found by regression analysis were older age, not being in school, impaired family functioning, HIV-related stigma and bullying, and poverty. Social support and parental competence were protective factors. Mental health problems among HIV-positive adolescents are highly prevalent and should be addressed as part of regular HIV care., (© The Author(s) 2020.)

Background: Mental disorders can adversely affect HIV treatment outcomes and survival. Data are scarce on premature deaths in people with mental disorders in HIV-positive populations, particularly in low-income and middle-income countries. In this study, we quantified excess mortality associated with mental disorders in HIV-positive people in South Africa, adjusting for HIV treatment outcomes., Methods: For this cohort study, we analysed routinely collected data on HIV-positive adults receiving antiretroviral therapy (ART) in Cape Town, South Africa between Jan 1, 2004, to Dec 31, 2017. Data from three ART programmes were linked with routine medical records on mental health treatment from Jan 1, 2010, to Dec 31, 2017, and mortality surveillance data from the South African National Population Register up to Dec 31, 2017. People living with HIV aged 15 years or older who initiated ART at a programme site were eligible for analysis. We followed up patients from ART initiation or Jan 1, 2010, whichever occurred later, to transfer, death, or Dec 31, 2017. Patients were considered as having a history of mental illness if they had ever received psychiatric medication or been hospitalised for a mental disorder. We calculated adjusted hazard ratios (aHRs) with 95% CIs for associations between history of mental illness, mortality, and HIV treatment outcomes (retention in care with viral load suppression [VLS; viral load <1000 copies per mL], retention in care with non-suppressed viral load [NVL; viral load ≥1000 copies per mL], and loss to follow-up [LTFU; >180 days late for a clinic visit at closure of the database]) using Cox proportional hazard regression and multistate models., Results: 58 664 patients were followed up for a median of 4·3 years (IQR 2·1-6·4), 2927 (5·0%) of whom had a history of mental illness. After adjustment for age, sex, treatment programme, and year of ART initiation, history of mental illness was associated with increased risk of mortality from all causes (aHR 2·98 [95% CI 2·69-3·30]), natural causes (3·00 [2·69-3·36]), and unnatural causes (2·10 [1·27-3·49]), compared with no history of mental illness. Risk of all-cause mortality in people with a history of mental illness remained increased in multivariable analysis adjusted for age, sex, treatment programme, year of ART initiation, CD4 count and WHO clinical stage at ART initiation, retention in HIV care with or without VLS, and LTFU (2·73 [2·46-3·02]). In our multistate model, adjusted for age, sex, year of ART initiation, cumulative time with NVL, and WHO clinical stage and CD4 cell count at ART initiation, rates of excess all-cause mortality in people with history of mental illness were greatest in patients retained in care with VLS (aHR 3·43 [95% CI 2·83-4·15]), followed by patients retained in care with NVL (2·74 [2·32-3·24]), and smallest in those LTFU (2·12 [1·78-2·53]). History of mental illness was also associated with increased risk of HIV viral rebound (transitioning from VLS to NVL; 1·50 [1·32-1·69]) and LTFU in people with VLS (1·19 [1·06-1·34])., Interpretation: Mental illness was associated with substantial excess mortality in HIV-positive adults in Cape Town. Excess mortality among people with a history of mental illness occurred independently of HIV treatment success. Interventions to reduce excess mortality should address the complex physical and mental health-care needs of people living with HIV and mental illness., Funding: National Institutes of Health, Swiss National Science Foundation, South African Medical Research Council., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Individuals with post-traumatic stress disorder (PTSD) evidence increased rates of metabolic syndrome (MetS), and both PTSD and MetS are associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Few investigations have examined the possible role of HPA-axis dysfunction in the co-occurrence of PTSD and MetS. In a case-control study, we aimed to determine whether hair cortisol concentrations (HCC) were associated with (i) PTSD caseness and severity and (ii) PTSD and MetS co-occurrence. We used the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) to determine PTSD diagnoses and severity scores in 216 females of mixed ancestry aged between 20 and 79 years ( M  = 43.8, SD =13.3). Hair samples, representing a three-month retrospective window of cortisol levels, were obtained and analyzed utilizing liquid chromatography-tandem mass spectrometry. We constructed multivariate linear regression models to evaluate whether PTSD diagnosis, PTSD severity, and MetS comorbidity were associated with HCC, controlling for potential confounders. HCC were significantly higher (adj β  = 0.154, p  = .033; Cohen's d  = 0.44) in PTSD patients ( n  = 110) than trauma-exposed controls ( n  = 106) and CAPS severity scores (adj β  = 0.207, p  = .005) were significantly associated with HCC. MetS was not associated with HCC and there were no significant interactions between PTSD and MetS on HCC. This study provides evidence of a chronically dysregulated neuroendocrine mediated stress response in PTSD, with a clear dose-response relationship. HCC do not, however, appear to have specificity for the comorbidity of PTSD and MetS in this sample.LAY SUMMARYWe found that levels of the stress hormone, cortisol, measured in hair samples were significantly higher in South African women with post-traumatic stress disorder (PTSD) than in women who had also experienced trauma but did not have PTSD. Hair cortisol levels were, however, not associated with metabolic syndrome, a cluster of risk factors for heart disease, in the women studied. We thus show that South African women with PTSD have elevated long-term stress hormone levels and that this effect is related to PTSD and not solely due to trauma exposure.

Background: Parkinson's disease (PD) and metabolic syndrome (MetS) share certain pathophysiological pathways, including hypothalamic pituitary adrenal (HPA) axis dysfunction. Hair glucocorticoid (GC) levels reflect longer-term HPA-axis function and can provide additional insights into the role of a dysregulated HPA-axis in PD and co-occurring cardiovascular disease (CVD) risk., Objectives: In a case-control study we examined the association of PD diagnosis, clinical features and PD-CVD risk (as defined by the MetS) co-occurrence with hair GC (cortisol and cortisone) levels., Methods: Hair samples, representing a three-month retrospective window of GC levels, were collected and analysed utilizing liquid chromatography tandem mass spectrometry in 56 females (25 PD patients and 31 controls) of mixed ancestry, aged between 45 and 78 years (PD patients, M = 64.5, SD = 8.4; controls, M = 55.7, SD = 6.9). Multivariate regression models were constructed with PD diagnostic status, clinical features and MetS comorbidity regressed on hair GC levels, adjusting for potential confounders., Results: The prevalence of MetS was 56.0 % in PD patients and 25.8 % in controls. Hair cortisone (adj B = 5.44, 95 % CI 2.05; 8.83, p =  0.002), but not hair cortisol levels (adj B = 0.05, 95 % CI -0.12; 0.22, p =  0.539), were significantly higher (Cohen's d = 0.87) in PD patients than in controls. Non-motor symptoms of PD (e.g., mood and anxiety) were significantly associated with hair cortisone levels (adj B = 0.29, 95 % CI 0.07; 0.51, p =  0.014). MetS was not associated with hair GC levels and there were no significant interactions between PD and MetS on hair GC levels., Conclusions: This study is the first study reporting on hair GC levels in PD. We found chronically increased cortisone, but not cortisol, levels in PD patients compared to controls. Furthermore, hair cortisone levels were significantly positively associated with PD symptoms related to mood, anhedonia, and anxiety. Hair GC levels were not associated with PD-MetS comorbidity in this sample. Hair cortisone levels may provide additional insights into HPA-axis dysfunction in PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Hair cortisol concentrations (HCC) are increasingly used as a biomarker of stress, however limited research exists regarding the relationship between HCC and protective factors, such as resilience. Additionally, studies measuring HCC need to account for possible confounders, and these factors have not been examined in sufficiently diverse settings., Objectives: Our objectives were to identify determinants of HCC in a sample of mixed ancestry adults and investigate the association of HCC with measures of self-perceived stress and resilience., Methods: Our sample comprised 164 females (mean age 46.5 years, SD = 15.0), self-identifying as mixed ancestry, who were control participants in a case-control study (SHARED ROOTS), conducted in Cape Town, South Africa from May 2014 until June 2017. We examined which socio-demographic, hair related, clinical and behavioural factors were associated with HCC in both unadjusted and adjusted linear regression models. Furthermore, the relationship of HCC with self-perceived stress and resilience scores were also examined., Results: HCC (Mdn 4.4 pg/ml; IQR 2.8; 11.4) were significantly positively associated with hair product use and breastfeeding, and significantly negatively associated with age, level of education, duration of sun exposure, duration of storage, and demonstrated a trend towards significance with frequency of hair washing, in adjusted models. HCC were inversely associated with CD-RISC scores (adj β = -0.179, p =  0.012) but were not significantly associated with PSS scores (adj β = -0.001, p =  0.989)., Conclusions: We identified specific determinants of HCC in our sample, including the first indication that sun exposure has an effect on HCC under naturalistic conditions. These potential confounders need to be controlled for in the design and analysis of future studies. HCC may be a biomarker of resilience to stress, rather than perceived stress. Further research measuring HCC in more diverse settings and populations and including constructs related to resilience are needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2019. Published by Elsevier Ltd.)

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.

Background: HIV-infected children and adolescents (CA-HIV) face significant mental health challenges related to a broad range of biological and psychosocial factors. Data are scarce on the agreement and discrepancy between caregivers and CA-HIV regarding emotional and behavioral problems (EBPs) in CA-HIV. Objectives: We determined agreement between self- versus caregiver- reported EBPs and describe factors associated with informant discrepancy among caregiver-youth dyads who participated in the "Mental health among HIV-infected CHildren and Adolescents in KAmpala and Masaka, Uganda" (CHAKA) study. Methods: In a cross-sectional sample, caregiver-reported EBPs were assessed with the Child and Adolescent Symptom Inventory-5 (CASI-5), and self-reported problems were evaluated with the Youth Inventory-4 (YI-4) in 469 adolescents aged 12-17 years and the Child Inventory-4 (CI-4) in 493 children aged 8-11 years. Adolescents were questioned about experiences of HIV stigma. Caregiver psychological distress was assessed with the Self-Reporting Questionnaire (SRQ-20). Linear regression models were applied to identify variables associated with discrepancy scores. Results: Self-reported emotional problems (EPs) were present in 28.8% of adolescents and 36.9% of children, and 14.5% of adolescents self-reported behavioral problems (BPs). There was only a modest correlation ( r ≤ 0.29) between caregiver- and CA-HIV-reported EBPs, with caregivers reporting more EPs whereas adolescents reported more BPs. Informant discrepancy between adolescents and caregivers for BPs was associated with adolescent age and caregiver's employment and HIV status. Among adolescents, EP discrepancy scores were associated with adolescent's WHO HIV clinical stage, caregiver level of education, and caregivers caring for other children. Among children, EP discrepancy scores were associated with child and caregiver age, caregiver level of education, and caregiver self-rated health status. HIV stigma and caregiver psychological distress were also associated with discrepancy, such that adolescents who experienced HIV stigma rated their EPs as more severe than their caregivers did and caregivers with increased psychological distress rated EBPs as more severe than CA-HIV self-rated. Conclusions: EBPs are frequently endorsed by CA-HIV, and agreement between informants is modest. Informant discrepancy is related to unique psychosocial and HIV-related factors. Multi-informant reports enhance the evaluation of CA-HIV and informant discrepancies can provide additional insights into the mental health of CA-HIV.

Background: Posttraumatic stress disorder (PTSD) is a disorder that develops following exposure to severely stressful events. Altered cortisol secretion has been reported in PTSD; however, results have been inconsistent. Previous meta-analyses of cortisol levels in PTSD have combined results of studies that have used different tissue samples (blood, saliva, urine) for cortisol measurement and have not included newer methods of determining cortisol levels (e.g. hair samples). In this systematic review, we will synthesise evidence from studies evaluating basal cortisol levels in PTSD patients versus controls and stratify studies according to tissue type used for cortisol measurement. We will also determine whether results from different tissue types can be pooled and if any specific tissue samples have better utility in research studies on PTSD., Methods: We will perform a systematic review of the scientific literature including all studies that have evaluated basal or baseline cortisol levels in adults with current PTSD versus controls, with and without trauma exposure. Independent reviewers will conduct searches in electronic databases (Medline, CINAHL, PTSDpubs, Web of Science, Scopus, ProQuest Dissertations & Theses A&I, ClinicalTrials.gov, and ICTRP), and additional studies will be obtained by searching the reference lists of articles. Two reviewers (LLvdH and SW) will independently conduct standardised screening, eligibility assessments, data extraction, and quality assessments before qualitative and, if appropriate, quantitative (meta-analysis and meta-regression) synthesis. Disagreements that arise at any stage will be resolved by a third reviewer (ShS)., Discussion: In line with previous reviews, we expect that cortisol levels will be lower in PTSD patients than in controls, but that patterns may vary somewhat according to the tissue sample in which cortisol is measured. This systematic review will assist in developing a better understanding of the acute and chronic patterns of basal cortisol secretion in PTSD and will inform future research., Systematic Review Registration: PROSPERO CRD42018091874.

Objective: Inadequate immunoregulation and elevated inflammation may be risk factors for posttraumatic stress disorder (PTSD), and microbial inputs are important determinants of immunoregulation; however, the association between the gut microbiota and PTSD is unknown. This study investigated the gut microbiome in a South African sample of PTSD-affected individuals and trauma-exposed (TE) controls to identify potential differences in microbial diversity or microbial community structure., Methods: The Clinician-Administered PTSD Scale for DSM-5 was used to diagnose PTSD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Microbial DNA was extracted from stool samples obtained from 18 individuals with PTSD and 12 TE control participants. Bacterial 16S ribosomal RNA gene V3/V4 amplicons were generated and sequenced. Microbial community structure, α-diversity, and β-diversity were analyzed; random forest analysis was used to identify associations between bacterial taxa and PTSD., Results: There were no differences between PTSD and TE control groups in α- or β-diversity measures (e.g., α-diversity: Shannon index, t = 0.386, p = .70; β-diversity, on the basis of analysis of similarities: Bray-Curtis test statistic = -0.033, p = .70); however, random forest analysis highlighted three phyla as important to distinguish PTSD status: Actinobacteria, Lentisphaerae, and Verrucomicrobia. Decreased total abundance of these taxa was associated with higher Clinician-Administered PTSD Scale scores (r = -0.387, p = .035)., Conclusions: In this exploratory study, measures of overall microbial diversity were similar among individuals with PTSD and TE controls; however, decreased total abundance of Actinobacteria, Lentisphaerae, and Verrucomicrobia was associated with PTSD status.

The aim of this study was to evaluate the frequency of, and factors associated with, postpartum hypomania (PPH) and postpartum depression (PPD) in a South African sample. Data from 57 women were analysed as part of a larger prospective study of maternal stress in pregnancy. On day 3 postpartum, women were assessed for probable PPH using the Highs scale. On day 3 and at week 6, probable PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS), while social support was evaluated using the Multidimensional Scale of Perceived Social Support (MSPSS). PPH was present in 49.1% of the participants at day 3 postpartum whilst PPD was present in 33.3% of participants on day 3 postpartum and in 45.6% at week 6. Participants meeting the clinical cut-off for both PPH and PPD on day 3 (17.5%) had significantly higher depression scores at week 6 than those with only PPH (p = 0.010) or only PPD (p = 0.035) on day 3. Depression scores on day 3 and lower social support scores at week 6 were predictive of PPD at week 6. Consistent with findings in other settings, early-onset PPD and poor social support were predictive of persisting PPD (i.e. at week 6). Women meeting criteria for both PPH and PPD on day 3 had greater depressive symptomatology at week 6. This may be indicative of an underlying bipolar disorder and warrants further investigation.

Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene (FTO), leptin and leptin receptor genes (LEP, LEPR), methylenetetrahydrofolate reductase (MTHFR) gene and the serotonin receptor 2C gene (HTR2C). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In this review we synthesised current literature on the psychopharmacological management of eating disorders (EDs) in children and adolescents (C&As). We focus specifically on anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED). The treatment of EDs is determined by physical and psycho-social factors and needs. Pharmacological management should therefore be viewed and incorporated as one component of a multi-disciplinary comprehensive treatment plan for specific requirements of a patient depending on the stage of the disorder. As there is a dearth of studies evaluating the use of psychopharmacology for EDs in C&As we first review the findings from studies performed in adults and then discuss specific studies performed in C&As. We include information from reviews and treatment guidelines to assist the clinician with an approach to the use of psychopharmacological agents in the treatment of EDs in C&As.