Dan J. Stein

Transcriptomic Network Analysis Reveals Trauma Type– and Ancestry-Related Heterogeneity in Posttraumatic Stress Disorder

OBJECTIVE: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that frequently co-occurs with major depressive disorder (MDD), a comorbidity that is partly attributable to shared genetic heritability and common environmental risk factors. Despite extensive efforts to identify peripheral transcriptomic biomarkers, findings have been inconsistent, potentially reflecting the substantial biological heterogeneity underlying these disorders. The primary goal of this study was to identify molecular signatures that reflect the clinical and biological heterogeneity of PTSD and MDD. METHODS: The authors present a network analysis of blood-based transcriptomics from 466 pregnant women in South Africa, including 215 individuals with PTSD and/or MDD (mean age, 26.34 years [SD=5.77]) and 251 trauma-exposed control participants (mean age, 27.14 years [SD=5.82]). Gene expression modules associated with trauma-related phenotypes were identified, including childhood adversity, intimate partner violence, and recent life stress, as well as ancestry and depressive symptoms, highlighting multiple sources of molecular variation. To evaluate the predictive relevance of these transcriptomic features, random forest models were applied using a nested cross-validation framework with permutation testing. RESULTS: Models achieved moderate and statistically significant performance in predicting trauma-related phenotypes (mean area under the receiver operating characteristic curve [AUROC], ~0.61-0.69 across models [SD=0.07-0.10]), whereas prediction of PTSD or MDD diagnosis showed near-chance performance (mean AUROC=0.52, SD=0.03). CONCLUSIONS: These findings suggest that peripheral blood transcriptomic signatures are more strongly associated with trauma exposure profiles and population background than with diagnostic status. Collectively, the results support exposure-informed stratification as a complementary framework to traditional diagnostic categories for capturing biologically meaningful heterogeneity.

Evaluation of Our Family Our Future: A Randomized Clinical Trial of a Family Resilience Intervention to Prevent Adolescent HIV/STI Infection and Depression in South Africa

Adolescents account for the majority of new HIV infections in South Africa and those with depressive symptoms are at elevated risk. Engaging families in preventive efforts is vital, but no effective interventions in South Africa integrate a family-based approach to adolescent HIV/STI prevention and depression. We report on results from a randomized controlled trial (RCT) testing the efficacy of Our Family Our Future , a family resilience intervention designed to address adolescent risk for depression, HIV and STIs. 879 adolescents (ages 14–16) in a high HIV prevalence urban setting near Cape Town, South Africa participated in a 2-arm, parallel, single-blinded RCT. Adolescents (along with one adult family member) were randomized to Our Family Our Future or to a control group. This analysis evaluates the intervention’s efficacy in reducing (1) depressive symptoms, (2) HIV/STI incidence, (3) sexual debut, rates of vaginal and anal sex, and condomless sex. Data were collected via smartphone at baseline, 6 and 12 months. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale; HIV was gathered through dried blood spot samples, STIs through urine samples; vaginal sexual debut, anal sexual debut, rates of vaginal and anal sex, and condomless sex was gathered through self-report. A post-hoc analysis examined the “dosage” effect of session attendance on outcomes. Of 879 adolescents, 444 were randomized to the control group and 435 to the intervention. Retention rates were 81–84% at 6 months and 90–98% at 12 months. Intervention participants completed 88–98% of their assigned sessions. Primary outcomes showed no significant differences in HIV/STI incidence or most sexual behaviors at 6 or 12 months, but vaginal sex prevalence was lower in the intervention group at 12 months (55% vs. 65%, p = 0.007). Condom use and sexual debut rates were similar between groups. Depression scores were higher in the intervention group at 6 months ( p = 0.004) but not at 12 months. Session attendance had no significant impact on depression or sexual behavior outcomes. Our Family Our Future showed mixed efficacy. The intervention reduced the number of adolescents engaging in vaginal sex at 12 months but had no effect on delaying sexual debut, reducing unprotected sex, or HIV/STI acquisition. Depression scores did not differ between groups at 12 months. Despite these mixed results, the reduction in sexual risk behavior suggests that family-based interventions hold promise and warrant further development.

MurrayFaculty of Health; Institute of Health and Biomedical Innovation

Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013: quantifying the epidemiological transition

Background The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age–sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development. Methods We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time. Findings Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6–6·6), from 65·3 years (65·0–65·6) in 1990 to 71·5 years (71·0–71·9) in 2013, HALE at birth rose by 5·4 years (4·9–5·8), from 56·9 years (54·5–59·1) to 62·3 years (59·7–64·8), total DALYs fell by 3·6% (0·3–7·4), and age-standardised DALY rates per 100¿000 people fell by 26·7% (24·6–29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non–communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries. Interpretation Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

Stein

Big data and psychiatry: advances, constraints and future directions.

Early work in psychiatry research, often involving single sites, small samples, and limited variables, has shifted to contemporary research involving multiple sites, large samples, and many variables. Such research raises important questions, including concerns about data quality and methodological rigor, uncertainty about its key lessons, issues regarding clinical relevance, and questions about how to optimize future advances. Here we consider these questions and concerns against the context of big data work on community and register-based surveys, cohort and biobank studies, electronic health records, digital phenotyping, brain imaging, genomics and other -omics, and randomized controlled trials. The development of large datasets allowing well-powered analyses is a major milestone, but sample size alone does not guarantee more precise estimates, and ongoing attention to the quality and rigor of big data collation and analysis is needed. Big data research has fostered trans-disciplinarity and given insights into mechanisms underlying psychiatric disorders, but also emphasizes the intricacy, heterogeneity and variability of such mechanisms, and the importance of triangulating between large-scale and small-scale research. The complexity of psychiatric phenotypes and psychobiological mechanisms contributes to the difficulty in bridging from big data to clinical application; big data research reinforces the importance of holding our diagnoses of psychiatric disorders lightly and providing explanations of these conditions humbly; and future work needs to be more attentive to clinical issues. There is enormous scope for further building databases relevant to psychiatry, but advances in conceptual models and asking the right questions are equally valuable. The full impact of big data, including artificial intelligence analyses, remains to be seen, but overenthusiastic support should be tempered by a better understanding of its strengths and limitations. At its best, such work will contribute in an iterative and integrative way to advancing our knowledge of psychiatric disorders and mental health.

Inhibitory control and error processing in Obsessive-Compulsive Disorder: A mega-analysis of task-based fMRI data by the ENIGMA-OCD consortium

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic condition in which impaired inhibitory control and excessive error monitoring may contribute to maintenance of obsessions and compulsions. This mega-analysis investigates neural activation during response inhibition and error processing using adult (OCD=563; control=348) and child (OCD=83, control=114) data from the ENIGMA-OCD consortium and the ABCD study (probable OCD=343; control=361). METHODS: Individual participant data was uniformly processed using HALFpipe to extract statistical maps for response inhibition and error processing contrasts. Bayesian multilevel models were used to assess regional and whole-brain effects of OCD, and to examine the association between the OCD clinical profile and task-related activation. RESULTS: Across inhibitory control tasks, both OCD and control participants showed robust activation in regions implicated in response inhibition and error processing. During response inhibition, compared to controls, adults with OCD showed stronger somatomotor cortex activation, while children with OCD showed stronger occipital cortex activation. Children with probable OCD from the ABCD cohort showed weaker activity in the frontoparietal network in the anterior insula/frontal operculum region. During error processing, relative to controls, adults with OCD showed weaker activation in fronto-striatal regions, while children with OCD showed stronger activation in frontoparietal and attention networks. Greater OCD symptom severity was associated with weaker task-related activation in adults and stronger activation in children during response inhibition. CONCLUSION: Case-control differences in brain activation during inhibitory control varied by age group and task contrast. Symptom severity emerged as the main clinical correlate of activation during inhibition, suggesting that inhibitory control deficits in OCD may be both state-dependent and developmentally specific.

Genome-wide analysis of social behaviour across social domains, reporters and developmental stages: a meta-regression approach

Social behaviour is a heritable trait linked to well-being and mental health, yet it varies across social context, including social domains, informants and development, which may shape its underlying genomic architecture. Here, we conducted a genome-wide meta-regression meta-analysis of social behaviour from infancy to early adulthood, studying ~500,000 repeated measures in European-ancestry cohorts ( N = 73,321). We modelled heterogeneity in single-variant associations across social domains (low prosocial behaviour and peer/social difficulties), multiple informants (parents, teachers and self-reports) and ages (2–29 years), identifying 6 associated loci, including variation within CADM2 ( P = 2.51 × 10 −9 ). Single nucleotide polymorphism-based heritability ranged from 2% to 7%, and the genetic architecture comprised 4 factors reflecting differences in either social domains or informants. Polygenic scores ( N = 16,305) accurately predicted contextual variation in independent cohorts, with some cross-ancestry transferability. Context-specific patterns of genetic correlations, particularly when estimating the developmental onset of associations, offer opportunities to disentangle shared trajectories linking social behaviour with later-life and mental health outcomes.

PatelThe Lancet

The Lancet Commission on global mental health and sustainable development

Predicting cognitive-behavioral therapy outcomes in obsessive-compulsive disorder from inhibitory control neural activity: A mega-analysis and machine learning study from the ENIGMA-OCD consortium

Objective Cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD), yet it remains difficult to predict who will respond. This study investigates associations between neural activity during inhibitory control tasks and CBT outcomes, and its value as a predictive marker of CBT outcome. Methods Using fMRI data from individuals performing an inhibitory control task across five ENIGMA-OCD samples (n=130, age range=8-57, 54% female), mass-univariate associations were analyzed between response inhibition and error processing activity and three CBT outcomes: response, remission, and change in symptom severity. Random forest classifier and support vector machine models using leave-one-sample-out and 5-fold cross-validation were used to predict CBT response and remission from fMRI activity and clinical data. Results Remission after CBT was associated with weaker activity in default mode regions during response inhibition and in the right supramarginal gyrus during error processing. Greater symptom reduction was linked to weaker pre-treatment activity across frontoparietal, dorsal attention, visual, and subcortical regions during response inhibition, and stronger default mode activity during error processing. These group-level effects were partially confirmed with machine learning, which predicted CBT response using inhibitory and error-related activity with modest AUC values of 0.66-0.67. Prediction of CBT remission or using other data types did not exceed chance-level. Conclusion Wide-spread weaker activity during response inhibition and stronger activity in default mode regions during error processing pre-treatment appear beneficial for CBT. Despite modestly predictive AUC-values, these findings cannot yet be translated into clinically relevant individual markers of CBT outcome.

Risk factors for major depressive disorder among adults recruited from hospital settings in Uganda, Kenya, Ethiopia and South Africa

Demographic and clinical characteristics of participants in the Neuropsychiatric Genetics of African Populations-Psychosis (NeuroGAP-Psychosis) study: A descriptive analysis

Prenatal Alcohol and/or Tobacco Exposure, White‐Matter Microstructure, and Cognition: Analyzing a South African Birth Cohort With Neurite Orientation and Dendrite Dispersion Imaging

BACKGROUND: Prenatal exposure to alcohol (PAE) and/or tobacco (PTE) may impact neurobiological and cognitive development years after such exposures have occurred. While such effects on cortical gray matter and cognition are widely researched, there is less research on the effects of PAE and PTE on white-matter development and cognition, particularly in non-clinical, community samples. METHODS: We analyzed white-matter microstructure and its cognitive correlates in four hundred and sixty five 8-12-year-olds in the urban Cape Town region of South Africa: 192 were prenatally exposed to alcohol and tobacco (PAE + PTE), 73 to tobacco only (PTE), 102 to alcohol only (PAE), and 98 to neither tobacco nor alcohol (CON). White-matter microstructure was quantified via neurite orientation and dendrite dispersion imaging (NODDI). The outcome variables were fractional anisotropy (FA), the neurite density index (NDI), and neurite orientation dispersion index (ODI) for 52 white-matter tracts. Cognition was measured using the Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V). RESULTS: PAE (but not PTE) was associated with NDI in 35 of 52 white-matter tracts analyzed. There were no false-discovery-rate (FDR) corrected main effects of PAE or PTE on FA or ODI. For 17 of the 35 tracts affected by PAE, the corresponding NDIs were positively associated with scores on the WISC-V Processing Speed Index. CONCLUSIONS: Our previous research of neuroanatomical structure in this cohort suggested that there are stronger effects of PTE on cortical gray matter. In contrast, the present data suggest that PAE may have stronger associations with white-matter microstructure, with such effects potentially manifesting as downstream deficits in processing speed.

Association of early life adversity with internalizing and externalizing behavior across 3 low- and middle-income countries

A blended genome and exome sequencing method captures genetic variation in an unbiased and cost-effective manner

Genome-wide association studies of infant and toddler temperament in European and multi-ancestry populations

In-utero HIV exposure and postnatal growth to 8 years of age: a prospective cohort study in the Western Cape, South Africa

BACKGROUND: The global scale-up of antiretroviral therapy for people living with HIV has led to an increase in children who are HIV-exposed uninfected (HEU), almost a quarter of whom lived in South Africa in 2024. These children might have suboptimal growth compared with children who are HIV-unexposed (HU), but few data are available beyond early childhood. We therefore evaluated differences in anthropometry by HIV exposure status from birth or from age 6 weeks, up to 8 years. METHODS: The Drakenstein Child Health Study-a prospective, longitudinal cohort study in the Western Cape of South Africa-recruited adult (age ≥18 years) women with and without HIV at 20-28 weeks' gestation from two primary health-care centres during routine antenatal care. Women and their liveborn children were followed up at least annually until age 8 years. The primary outcome was differences in anthropometry at birth or age 6 weeks and postnatally by HIV exposure, which was assessed at least annually by trained study staff and converted to sex-specific weight-for-age Z scores (WAZ), length-for-age or height-for-age Z scores (HAZ), and BMI-for-age Z scores (BMIZ) per WHO growth standards. All outcomes were assessed in all children with anthropometry data after birth. Stunting (HAZ <-2 SD from age 12 months) and overweight (BMIZ >2 SD from age 6 months) were secondary outcomes. Mixed-effects models adjusted for size at birth and prenatal covariates were used to estimate overall and age-specific associations between in-utero HIV-exposure status and WAZ, HAZ, BMIZ, stunting, and overweight from age 6 weeks to 8 years. FINDINGS: 1225 pregnant women were enrolled from March 5, 2012, to March 31, 2015. 88 women were ineligible or withdrew and the remaining 1137 delivered 1143 livebirths, of whom 71 children were ineligible or withdrew. The remaining 1072 children (HEU 236 [22·0%] vs HU 836 [78·0%]) were enrolled and followed up until age 8 years. Mean birthweight was 3035 g (SD 592; HEU 3012 g [598] vs HU 3041 g [590]) and 168 (15·7%) of 1070 infants were preterm (HEU 43 [18·3%] of 235 vs HU 125 [15·0%] of 835). In overall multivariable estimates, children who were HEU had lower overall WAZ (marginal difference -0·16 [95% CI -0·32 to -0·01]) and HAZ (-0·26 [-0·41 to -0·11]) from age 6 weeks to 8 years compared with children who were HU. Age-specific differences were largest before age 6 months for WAZ and before age 3 years for HAZ. In overall multivariable estimates, there was no association between HIV exposure and BMIZ (-0·02 [-0·17 to 0·12]), stunting (0·05 [-0·04 to 0·13]), or overweight (-0·01 [-0·04 to 0·02]) from age 6 weeks to 8 years. INTERPRETATION: Compared with children who were HU, children who were HEU had lower overall WAZ and HAZ from age 6 weeks to 8 years, with the largest differences in early childhood. Early-life growth deficits are predictors of adverse health outcomes in later life; therefore, future work should focus on understanding the causes of growth deficits to improve health outcomes for children who are HEU. Interventions to optimise growth for all children in South Africa remain crucial.

Brain Aging in Specific Phobia: An ENIGMA ‐Anxiety Mega‐Analysis

Decomposing neuroanatomical heterogeneity in depression: insights from an ENIGMA major depressive disorder working group study in 5146 individuals

Pharmacotherapy for post traumatic stress disorder (PTSD)

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment. OBJECTIVES: To assess the effects of medication for reducing PTSD symptoms in adults with PTSD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 11, November 2020); MEDLINE (1946-), Embase (1974-), PsycINFO (1967-) and PTSDPubs (all available years) either directly or via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR). We also searched international trial registers. The date of the latest search was 13 November 2020. SELECTION CRITERIA: All randomised controlled trials (RCTs) of pharmacotherapy for adults with PTSD. DATA COLLECTION AND ANALYSIS: Three review authors (TW, JI, and NP) independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. We contacted investigators to obtain missing data. We stratified summary statistics by medication class, and by medication agent for all medications. We calculated dichotomous and continuous measures using a random-effects model, and assessed heterogeneity. MAIN RESULTS: We include 66 RCTs in the review (range: 13 days to 28 weeks; 7442 participants; age range 18 to 85 years) and 54 in the meta-analysis. For the primary outcome of treatment response, we found evidence of beneficial effect for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.74; 8 studies, 1078 participants), which improved PTSD symptoms in 58% of SSRI participants compared with 35% of placebo participants, based on moderate-certainty evidence. For this outcome we also found evidence of beneficial effect for the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine: (RR 0.45, 95% CI 0.22 to 0.94; 1 study, 26 participants) in 65% of people on mirtazapine compared with 22% of placebo participants, and for the tricyclic antidepressant (TCA) amitriptyline (RR 0.60, 95% CI 0.38 to 0.96; 1 study, 40 participants) in 50% of amitriptyline participants compared with 17% of placebo participants, which improved PTSD symptoms. These outcomes are based on low-certainty evidence. There was however no evidence of beneficial effect for the number of participants who improved with the antipsychotics (RR 0.51, 95% CI 0.16 to 1.67; 2 studies, 43 participants) compared to placebo, based on very low-certainty evidence. For the outcome of treatment withdrawal, we found evidence of a harm for the individual SSRI agents compared with placebo (RR 1.41, 95% CI 1.07 to 1.87; 14 studies, 2399 participants). Withdrawals were also higher for the separate SSRI paroxetine group compared to the placebo group (RR 1.55, 95% CI 1.05 to 2.29; 5 studies, 1101 participants). Nonetheless, the absolute proportion of individuals dropping out from treatment due to adverse events in the SSRI groups was low (9%), based on moderate-certainty evidence. For the rest of the medications compared to placebo, we did not find evidence of harm for individuals dropping out from treatment due to adverse events. AUTHORS' CONCLUSIONS: The findings of this review support the conclusion that SSRIs improve PTSD symptoms; they are first-line agents for the pharmacotherapy of PTSD, based on moderate-certainty evidence. The NaSSA mirtazapine and the TCA amitriptyline may also improve PTSD symptoms, but this is based on low-certainty evidence. In addition, we found no evidence of benefit for the number of participants who improved following treatment with the antipsychotic group compared to placebo, based on very low-certainty evidence. There remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.

Motivational interviewing for substance use among adults in low- and middle-income countries: A systematic review

Background: Harmful substance use (HSU) poses a significant global health challenge, impacting social, economic, and healthcare systems. Low- and middle-income countries (LMICs) are particularly burdened as a result of limited infrastructure for managing substance-related issues. While evidence-based brief interventions like motivational interviewing (MI) are widely used in high-income countries, research on their effectiveness in LMICs is limited. Aim: This systematic review aims to evaluate studies employing MI as part of interventions for adults with HSU in LMIC settings. Setting: This review focused on studies within low- and middle-income countries which include settings characterised by constrained mental health resources, high treatment gaps for substance use disorders (SUDs), and diverse service delivery contexts. Methods: Following Cochrane and PRISMA guidelines, we searched PubMed, EBSCOhost, Web of Science, Cochrane Library, clinicaltrials.gov and GSK Clinical Study Register for publications from 2010 to 2022. A narrative analysis was conducted, and the Joanna Briggs Institute Critical Appraisal Tools assessed study quality. Results: Out of 518 publications, 11 studies from five countries met our inclusion criteria. Most were randomised controlled trials, with some using qualitative or mixed methods. The interventions targeted alcohol, opioids, and other drugs. Different strategies were used, including MI-blended with other interventions (such as cognitive-behavioural therapy, behavioural activation, and imaginal desensitisation) or using MI-informed approaches. Conclusion: Overall, MI-informed interventions were shown to improve substance use outcomes in six of the 11 studies, with a significant reduction in substance use. However, further high-quality research with larger samples and rigorous designs is needed to strengthen the evidence base and address potential sources of bias. Contribution: Findings suggest that MI-informed approaches, as a brief intervention, can improve substance use outcomes in resource-constrained environments within LMICs.

Violence Exposure and Mental Health Problems Among School-Aged Children in a South African Birth Cohort

Objective: There is little longitudinal research investigating links between violence exposure and mental disorders among children in low- and middle-income countries (LMICs), despite high rates of violence. We examined cross-sectional and longitudinal violence-mental health associations among children in a large South African birth cohort, the Drakenstein Child Health Study, including direct clinical interviews capturing children's mental disorders. Method: =974), we assessed lifetime violence exposure and four subtypes (witnessed community, community victimization, witnessed domestic, domestic victimization) at ages 4.5 and 8-years via caregiver reports. At 8-years, caregivers completed the Child Behaviour Checklist; and psychiatric disorders were assessed using the Mini-International Neuropsychiatric Interview for Children and Adolescents, a self-report measure. We tested for associations using linear/logistic regressions, adjusted for confounders. Results: Most children (91%) had experienced violence by 8-years. Cross-sectionally, total violence exposure was associated with total (B =0.49 [95% CI 0.32, 0.66]), internalizing (0.32 [0.17, 0.47]), and externalizing problems (0.46 [0.31, 0.61]), and with increased odds of disorder at 8 years (aOR=1.09 [1.05, 1.13]). Longitudinally, total violence exposure up to 4.5-years was associated with total (B=0.27 [0.03, 0.52]), internalizing (0.24 [0.04. 0.44]), and externalizing scores (0.23 [0.008, 0.45]) at 8-years, but not with increased risk of psychiatric disorders. The strongest and most consistent associations were observed for domestic versus community violence subtypes. Conclusion: Our strong cross-sectional but weaker longitudinal findings suggest that recent violence exposures may be more critical than early exposures for children's mental health. Longitudinal exploration of other violence-affected LMIC populations is urgently needed.