Leigh van den Heuvel

A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia

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.

The Microbiome in Posttraumatic Stress Disorder and Trauma-exposed Controls: An Exploratory Study

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, &agr;-diversity, and &bgr;-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 &agr;- or &bgr;-diversity measures (e.g., &agr;-diversity: Shannon index, t = 0.386, p = .70; &bgr;-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.

Hippocampal and amygdala volumes in adults with posttraumatic stress disorder secondary to childhood abuse or maltreatment: A systematic review

We systematically reviewed differences in hippocampal and amygdala volumes between adults with childhood maltreatment-related posttraumatic stress disorder (PTSD) and healthy controls. Using the terms adults, MRI, magnetic resonance imaging, with posttraumatic stress disorder PTSD, child abuse, and child maltreatment, we conducted searches on several electronic databases. We identified 10 studies that met our inclusion criteria; 7 of which were included in a meta-analysis of hippocampal volume and 4 that were included in a meta-analysis of amygdala volume. Mean hippocampal and amygdala volumes were used to determine effect sizes. We found bilateral reduction of both the hippocampus and amygdala in the PTSD group compared to healthy controls, with effect sizes of -0.66 and -0.67 for the left and right hippocampus (p<0.00001 and p=0.002) and -1.08 and -1.15 for the left and right amygdala, (p=0.013 and p=0.003), respectively. Confidence intervals were -0.93,-0.39 and -1.26,-0.29 for the left and right hippocampus, respectively. For the amygdala, confidence intervals were -1.92,-0.23 and -1.19, -0.39 for the left and right amygdala. The relatively few studies available for analysis is a limitation. Additionally, sex diverse MRI studies in PTSD are needed to determine whether sex plays a significant role in the hippocampal effects associated with childhood-onset trauma.

Brain-derived neurotrophic factor Val66met polymorphism and plasma levels in road traffic accident survivors

ABSTRACT Background: Alterations in brain-derived neurotrophic factor (BDNF) expression and release may play a role in the pathogenesis of post-traumatic stress disorder (PTSD). Design: This study evaluated road traffic accident (RTA) survivors to determine whether PTSD and trauma-related factors were associated with plasma BDNF levels and BDNF Val66Met carrier status following RTA exposure. Methods: One hundred and twenty-three RTA survivors (mean age 33.2 years, SDu2009=u200910.6 years; 56.9% male) were assessed 10 (SDu2009=u20094.9) days after RTA exposure. Acute stress disorder (ASD), as assessed with the Acute Stress Disorder Scale, was present in 50 (42.0%) of the participants. Plasma BDNF levels were measured with enzyme-linked immunosorbent assay and BDNF Val66Met genotyping was performed. PTSD, as assessed with the Clinician-Administered PTSD Scale, was present in 10 (10.8%) participants at 6 months follow-up. Results: Neither BDNF Val66Met genotype nor plasma BDNF was significantly associated with the presence or severity of ASD or PTSD. Plasma BDNF levels were, however, significantly correlated with the lifetime number of trauma exposures. Conclusions: In RTA survivors, plasma BDNF levels increased with increasing number of prior trauma exposures. Plasma BDNF may, therefore, be a marker of trauma load.

Frequency and correlates of anxiety and mood disorders among TB- and HIV-infected Zambians

We determined the frequency and correlates of current common mental disorders (CMDs) in a consecutive series of 649 adult patients with human immunodeficiency virus (HIV), tuberculosis (TB) or both receiving treatment at 16 primary health care centres across Zambia. Data on socio-demographic variables, clinical disease features, anxiety and mood disorders were collected. The frequency of any anxiety disorder (AD) was 30.8% and major depressive disorder (MDD) 11.3%. Although differences by disease group did not reach statistical significance, rates of suicidality (34.8%) and panic disorder (4.1%) were highest for the TB–HIV group (n = 269), while rates of generalised AD (13.3%), obsessive compulsive disorder (7.6%), posttraumatic stress disorder (7.4%) and any AD (37.8%) were highest for the HIV group (n = 149). Female gender (p = 0.004) predicted any current AD as well as current suicidality (p = 0.009), while lower education status (p < 0.001) predicted current MDD. World Health Organisation (WHO) clinical staging and antiretroviral treatment status were not significantly associated with MDD or anxiety in the HIV and co-infected groups. This study indicates the importance of early identification of CMDs in TB, HIV and co-infected patients, especially women and uneducated patients, newly initiated on treatment in primary care settings.

Posttraumatic Stress Disorder, Overweight, and Obesity: A Systematic Review and Meta-analysis.

AbstractPrevious reports have suggested a high prevalence of overweight and obesity among individuals with posttraumatic stress disorder (PTSD). Few studies, however, systematically analyze the relationship between PTSD and body mass index (BMI). We conducted a systematic review and meta-analysis aimed at estimating the association between PTSD and BMI. Fifty-four articles were reviewed, 30 of which (with 191,948 individuals with PTSD and 418,690 trauma-exposed individuals or healthy controls) were eligible for inclusion in the meta-analysis. The pooled standard mean difference, based on a random-effects model, was 0.41 (95% confidence interval, 0.28–0.54; z = 6.26; p < .001). Statistical heterogeneity between the included studies was high (p < .001; I2 = 99%). Despite limitations, the findings of this systematic review and meta-analysis suggest an association between PTSD and BMI. Furthermore, longitudinal studies tentatively indicate that PTSD may lead to an increase in BMI and, as such, to the development of overweight/obesity, particularly in women. Further prospective studies and research elaborating the nature and etiology of the association are required.

Association of childhood maltreatment with internalising and externalising disorders in trauma-exposed adolescents

Introduction South African adolescents experience high levels of trauma, including various types of childhood maltreatment. Different types of maltreatment often co-occur. Previous research suggests that childhood maltreatment provokes a latent liability to internalising and externalising dimensions of psychopathology. Our objective was to examine the effects of childhood maltreatment on internalising and externalising disorders in trauma-exposed adolescents and to assess the mediating effect of post-traumatic stress disorder (PTSD) on these associations. Methods A cross-sectional study was conducted with 262 trauma exposed adolescents (aged 12–18 years) in South Africa. Childhood maltreatment and PTSD severity were assessed using the Childhood Trauma Questionnaire and the Child PTSD Checklist, respectively. Psychiatric disorders were diagnosed utilising the Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime version – and were grouped into internalising and externalising disorders. Hierarchal logistic regression was used to assess the association between childhood maltreatment types and internalising and externalising disorders, controlling for statistically significant socio-demographic characteristics, with PTSD severity added to the final model as a potential mediator. Results Sexual abuse was significantly associated with internalising disorders (B = 0.07, p = 0.011), although this effect was mediated by PTSD severity (B = 0.05, p = 0.001; not included as an internalising disorder). In contrast, physical abuse (B = 0.09, p = 0.004) and gender (B = 0.70, p = 0.035) were associated with externalising disorders, but the addition of PTSD severity did not significantly alter these associations. Conclusion The association between sexual abuse and internalising disorders was fully mediated by PTSD symptom severity. Gender and physical abuse severity, but not PTSD severity, was associated with the presence of externalising disorders. Adolescents displaying internalising or externalising psychopathology need to be assessed for exposure to childhood physical and sexual abuse and PTSD comorbidity.

Sleep quality and neurocognitive functioning in metabolic syndrome

Background The incidence of metabolic syndrome (MetS), a cluster of metabolic risk factors in a single individual, is increasing worldwide, making it important to study the possible risk and protective factors. Accumulating evidence has suggested sleep deprivation and/or fragmentation is among the key factors involved in the onset and treatment resistance of MetS components. Moreover, bidirectional associations between sleep complaints and MetS have been described. In addition, there is mounting evidence of the effect of MetS on cognitive functioning. Aims The aim of this study was to assess whether MetS and sleep complaints are associated with clinically determined neurocognitive disturbances in a sample of participants with MetS symptoms, ranging from none to all criteria met. Methods Participants comprised 153 mixed race individuals from the Western Cape province of South Africa. Sleep (Pittsburgh Sleep Quality Index), neurocognition (Repeatable Battery for the Assessment of Neuropsychological Status) and anthropometric (MetS components) assessments were performed on all participants. A hierarchical regression model, including potentially confounding variables (e.g. IQ), demographic variables (e.g. age and gender) and clinical variables (e.g. [BMI] and cholesterol), was then constructed. Results The model was significant: adjusted R square = 0.486; F(13, 110) = 9.952, p < 0.0001. The demographic variables accounted for 32.3% of variability. This increased to 48.5% when the clinical variables were added. Sleep and metabolic criteria only added 0.1%. Discussion Although we did not find sleep and metabolic factors to significantly influence cognition when other factors were accounted for, further investigation into risk and outcome factors, such as these, may assist in the identification of mechanistic links, which may also improve management of patients who are at risk, thereby improving health outcomes.

Validation of the Montreal cognitive assessment against the RBANS in a healthy South African cohort

Background Mild cognitive impairment (MCI) represents an intermediate state between normal cognition and dementia. Early detection and treatment of reversible contributing factors to progressive cognitive decline currently forms the cornerstone of management. As the population at risk of developing dementia is projected to increase significantly in many low- and middle-income countries where health care services continue to operate under clinical and human resource constraints, there is a need for low-cost, quick and reliable screening tools. The Montreal cognitive assessment (MoCA) was developed as a brief screening tool with high sensitivity and specificity for detecting MCI. The initial validation sample for the MoCA consisted of English and French speaking Canadians. Studies undertaken in a variety of countries show that the reliability and validity of the MoCA in screening for MCI is good; however, it has been recommended that some item modification and adjustment of cut-offs for the diagnosis of MCI in these populations may be needed to account for cultural differences. To date, no studies have evaluated the MoCA in the South African population. We aimed to compare the validity of the MoCA to the RBANS, evaluate the effectiveness of the MoCA as a screening tool for MCI and generate normative data for the MoCA. Methods A cross-sectional observational study comprising a sample of 370 cognitively healthy males and females aged 18 years and older of mixed race (Coloured ethnicity) who were administered the MoCA and RBANS during screening. Results The MoCA showed acceptable internal consistency (Cronbach’s alpha of 0.624). MoCA scores were significantly associated with gender (r = -0.199, p = 0.000), and correlated with age (r = -0.203, p = 0.000) and education (r = 0.326, p = 0.000). There was a strong correlation between total scores on the MoCA and RBANS (r = 513; p = 0.000), indicating good criterion-related validity. The MoCA also showed good agreement with the RBANS according to the Bland–Altman plot. ROC statistics demonstrated that the performance of the MoCA for predicting MCI compared to the RBANS was fair with an AUC of 0.794. Using the recommended cut-off score of 26, the MoCA showed high sensitivity (94.23%) but low specificity (28.16%). When the cut-off score was lowered to 23, the sensitivity was 75% and specificity 66.77%, while a cut-off of 24 demonstrated a sensitivity of 84.62% and a specificity of 52.53%. Conclusion Although the MoCA appears fairly reliable at identifying MCI in this population, our findings suggest that some modification to certain domains and items is needed to improve the differentiation between normal ageing and MCI. Until such time that a culturally adapted version of the MoCA has been developed and validated for this population, we suggest lowering the cut-off score to 24 in order to reduce false-positive diagnoses of MCI.

Reward processing dysfunction in ventral striatum and orbitofrontal cortex in Parkinson's disease

BACKGROUNDnParkinsons disease is a growing concern as the longevity of the worlds population steadily increases. Both ageing and Parkinsons disease have an impact on dopamine neurotransmission. It is therefore important to investigate their relative impact on the fronto-striatal reward system. There has been little investigation of reward processing in terms of anticipation and reward outcome in Parkinsons disease. Abnormal responses during reward processing have previously been demonstrated in whole-brain analysis of Parkinsons patients with mild lateralized disease, but the exact impact in regions specific to reward processing is still unknown.nnnOBJECTIVEnHere we aim to investigate the impact of Parkinsons disease on the orbitofrontal ventral striatal reward system in patients with moderate to severe clinical symptoms.nnnMETHODSnWe utilized a monetary incentive delay (MID) task in 17 Parkinsons patients who were compared to two control groups stratified by age. The MID paradigm reliably activates the ventral striatum during reward anticipation and the orbitofrontal cortex during reward outcome processing.nnnRESULTSnRelative to the two control groups, Parkinsons disease patients had abnormal task related activity during both reward anticipation in the ventral striatum and reward outcome in the orbitofrontal cortex. There were no effects of ageing.nnnCONCLUSIONnThese findings demonstrate abnormalities in anticipatory as well as reward outcome processing while treated primarily with levodopa. The orbitofrontal dysfunction during reward outcome processing may have specificity in Parkinsons disease, as it has been shown to be relatively unaffected by normal ageing.