Nastassja Koen

A 2012 Evidence-Based Algorithm for the Pharmacotherapy for Obsessive-Compulsive Disorder

There is a need to synthesize the growing body of literature on the pharmacotherapeutic management of patients with obsessive-compulsive disorder for clinicians working at a primary care level. We have aimed to generate a simple, easy-to-follow algorithm for the primary care practitioner. This seven-step algorithm addresses diagnosis of obsessive-compulsive disorder, initiation of pharmacotherapy, monitoring and maintenance treatment, and guidelines for the management of patients who are resistant to initial therapy. In creating this algorithm, we have drawn on the body of published evidence, as well as on expert opinion.

DICER1 and microRNA regulation in post-traumatic stress disorder with comorbid depression

DICER1 is an enzyme that generates mature microRNAs (miRNAs), which regulate gene expression post-transcriptionally in brain and other tissues and is involved in synaptic maturation and plasticity. Here, through genome-wide differential gene expression survey of post-traumatic stress disorder (PTSD) with comorbid depression (PTSD&Dep), we find that blood DICER1 expression is significantly reduced in cases versus controls, and replicate this in two independent cohorts. Our follow-up studies find that lower blood DICER1 expression is significantly associated with increased amygdala activation to fearful stimuli, a neural correlate for PTSD. Additionally, a genetic variant in the 3′ un-translated region of DICER1, rs10144436, is significantly associated with DICER1 expression and with PTSD&Dep, and the latter is replicated in an independent cohort. Furthermore, genome-wide differential expression survey of miRNAs in blood in PTSD&Dep reveals miRNAs to be significantly downregulated in cases versus controls. Together, our novel data suggest DICER1 plays a role in molecular mechanisms of PTSD&Dep through the DICER1 and the miRNA regulation pathway.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Investigating the psychosocial determinants of child health in Africa: the Drakenstein Child Health Study

BACKGROUND Early life psychobiological and psychosocial factors play a key role in influencing child health outcomes. Longitudinal studies may help elucidate the relevant risk and resilience profiles, and the underlying mechanisms that impact on child health, but there is a paucity of birth cohort data from low and middle-income countries (LMIC). We describe the rationale for and present baseline findings from the psychosocial component of the Drakenstein Child Health Study (DCHS). METHODS We review the psychosocial measures used in the DCHS, a multidisciplinary birth cohort study in a peri-urban area in South Africa, and provide initial data on psychological distress, depression, substance use, and exposure to traumatic stressors and intimate partner violence (IPV). These and other measures will be assessed longitudinally in mothers in order to investigate associations with child neurodevelopmental and health outcomes. RESULTS Baseline psychosocial data is presented for mothers (n=634) and fathers (n=75) who have completed antenatal assessments to date. The sample of pregnant mothers is characterized by multiple psychosocial risk factors, including a high prevalence of psychological distress and depression, high levels of substance use, and high exposure to traumatic stressors and IPV. DISCUSSION These data are consistent with prior South African studies which have documented a high prevalence of a multitude of risk factors during pregnancy. Further longitudinal assessment of mothers and children may clarify the underlying psychobiological and psychosocial mechanisms which impact on child health, and so inform clinical and public health interventions appropriate to the South African and other LMIC contexts.

Genome-wide gene-based analysis suggests an association between Neuroligin 1 ( NLGN1 ) and post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.

Risk Factors for Antenatal Depression and Associations with Infant Birth Outcomes: Results From a South African Birth Cohort Study

BACKGROUND Maternal antenatal depression may be particularly prevalent in low- and middle-income countries, but there is a paucity of data on its effect on birth outcomes in such settings. We investigated risk factors for antenatal depression and the associations between depression and infant birth outcomes in the Drakenstein Child Health Study (DCHS), a birth cohort study in the Western Cape, South Africa. METHODS The prevalence of depression in pregnant women enrolled in the DCHS from primary care antenatal clinics was measured using the Beck Depression Inventory (BDI-II). Predictors of antenatal depression were investigated using logistic regression, and the associations between depression and infant birth outcomes were examined in linear regression models. RESULTS Among 726 pregnant women (median age: 26 years), 156 (21%) had BDI-II scores suggesting depression. Independent predictors of depression included single marital status, low socioeconomic status (SES), recent stressful life events, unplanned pregnancy, childhood trauma, and past-year intimate partner violence. No association was observed between antenatal depression and preterm birth. Strong associations were observed between antenatal depression and decreased infant weight-for-age (WAZ) and head circumference-for-age (HCAZ) z-scores at birth. In multivariable analysis, the association between depression and decreased HCAZ remained significant, when adjusted for clinic, SES, and recent stressful life events. CONCLUSIONS Antenatal depression and associated risk factors are highly prevalent in this setting and are associated with adverse fetal growth. Maternal mental health may be an important predictor of infant growth in utero.

Intimate partner violence: associations with low infant birthweight in a South African birth cohort

Violence against women is a global public health problem. Exposure to intimate partner violence (IPV) during pregnancy has been associated with a number of adverse maternal and fetal outcomes, including delivery of a low birthweight (LBW) infant. However, there is a paucity of data from low-middle income countries (LMIC). We examined the association between antenatal IPV and subsequent LBW in a South African birth cohort. This study reports data from the Drakenstein Child Lung Health Study (DCLHS), a multidisciplinary birth cohort investigation of the influence of a number of antecedent risk factors on maternal and infant health outcomes over time. Pregnant women seeking antenatal care were recruited at two different primary care clinics in a low income, semi-rural area outside Cape Town, South Africa. Antenatal trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ) and an IPV assessment tool specifically designed for the purposes of this study. Potential confounding variables including maternal sociodemographics, pregnancy intention, partner support, biomedical and mental illness, substance use and psychosocial risk were also assessed. Bivariate and multiple regression analyses were performed to determine the association between IPV during pregnancy and delivery of an infant with LBW and/or low weight-for-age z (WAZ) scores. The final study sample comprised 263 mother-infant dyads. In multiple regression analyses, the model run was significant [r2 = 0.14 (adjusted r2 = 0.11, F(8, 212) = 4.16, p = 0.0001]. Exposure to physical IPV occurring during the past year was found to be significantly associated with LBW [t = −2.04, p = 0.0429] when controlling for study site (clinic), maternal height, ethnicity, socioeconomic status, substance use and childhood trauma. A significant association with decreased WAZ scores was not demonstrated. Exposure of pregnant women to IPV may impact newborn health. Further research is needed in this field to assess the relevant underlying mechanisms, to inform public health policies and to develop appropriate trauma IPV interventions for LMIC settings.

Antenatal and early life tobacco smoke exposure in an African birth cohort study.

BACKGROUND Exposure to tobacco smoke in African infants has not been well studied, despite the high burden of childhood respiratory disease in these communities. OBJECTIVE To investigate the prevalence of antenatal and early life tobacco smoke exposure and associations with infant birth outcomes in an African birth cohort, the Drakenstein Child Health Study. METHODS Self-report questionnaires assessing maternal and household smoking were administered. Maternal and infant urine cotinine testing was conducted antenatally, at birth and at 6-10 weeks of life to measure tobacco smoke exposure. Multivariate regression models explored the associations between exposure to smoke and infant birth outcomes. RESULTS Of 789 pregnant women included, 250 (32%) were active smokers on cotinine testing. At birth and at 6-10 weeks of life, respectively 135/241 (56%) and 154/291 (53%) infants had urine cotinine levels indicating tobacco smoke exposure. Household smoking was prevalent and was associated with positive infant cotinine test results. Antenatal maternal smoking was associated with decreased infant birthweight-for-age Z-score (0.3, 95%CI 0.1-0.5). CONCLUSION Antenatal and early life tobacco smoke exposure is highly prevalent in this community, and may impact on birth outcomes and subsequent child health. Smoking cessation interventions are urgently needed to reduce tobacco smoke exposure in African communities.

A study of the effects of prenatal alcohol exposure on white matter microstructural integrity at birth.

Background Neuroimaging studies have indicated that prenatal alcohol exposure is associated with alterations in the structure of specific brain regions in children. However, the temporal and regional specificity of such changes and their behavioural consequences are less known. Here we explore the integrity of regional white matter microstructure in infants with in utero exposure to alcohol, shortly after birth. Methods Twenty-eight alcohol-exposed and 28 healthy unexposed infants were imaged using diffusion tensor imaging sequences to evaluate white matter integrity using validated tract-based spatial statistics analysis methods. Second, diffusion values were extracted for group comparisons by regions of interest. Differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity were compared between groups and associations with measures from the Dubowitz neonatal neurobehavioural assessment were examined. Results Lower AD values (p<0.05) were observed in alcohol-exposed infants in the right superior longitudinal fasciculus compared with non-exposed infants. Altered FA and MD values in alcohol-exposed neonates in the right inferior cerebellar were associated with abnormal neonatal neurobehaviour. Conclusion These exploratory data suggest that prenatal alcohol exposure is associated with reduced white matter microstructural integrity even early in the neonatal period. The association with clinical measures reinforces the likely clinical significance of this finding. The location of the findings is remarkably consistent with previously reported studies of white matter structural deficits in older children with a diagnosis of foetal alcohol spectrum disorders.

White matter microstructural integrity and neurobehavioral outcome of HIV-exposed uninfected neonates

AbstractThe successful implementation of prevention programs for mother-to-child human immunodeficiency virus (HIV) transmission has dramatically reduced the prevalence of infants infected with HIV while increasing that of HIV-exposed uninfected (HEU) children. Neuropsychological assessments indicate that HEU children may exhibit differences in neurodevelopment compared to unexposed children (HUU). Pathological mechanisms leading to such neurodevelopmental delays are not clear. In this observational birth cohort study we explored the integrity of regional white matter microstructure in HEU infants, shortly after birth.Microstructural changes in white matter associated with prenatal HIV exposure were evaluated in HEU infants (n = 15) and matched controls (n = 22) using diffusion tensor imaging and tract-based spatial statistics. Additionally, diffusion values were extracted and compared for white matter tracts of interest, and associations with clinical outcomes from the Dubowitz neonatal neurobehavioral tool were investigated.Higher fractional anisotropy in the middle cerebellar peduncles of HEU compared to HUU neonates was found after correction for age and gender. Scores on the Dubowitz abnormal neurological signs subscale were positively correlated with FA (r = 0.58, P = 0.038) in the left uncinate fasciculus in HEU infants.This is the first study to present data suggesting that prenatal HIV exposure without infection is associated with altered white matter microstructural integrity in the neonatal period. Longitudinal studies of HEU infants as their brains mature are necessary to understand further the significance of prenatal HIV and antiretroviral treatment exposure on white matter integrity and neurodevelopmental outcomes.