Browsing by Author "Stein, Dan"

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    Open Access
    A functional magnetic resonance imaging study of cognitive emotion regulation in relation to individual differences in self-esteem
    (2020) Swan, Freda Zoë; Groenewold, Nynke; Uhlmann, Anne; Stein, Dan
    Objectives Self-esteem may affect the processing and regulation of emotion. However, it is unclear whether differences in self-esteem are associated with changes in initial emotional appraisal or engagement of emotion regulation. I investigated whether individual differences in self-esteem predicted brain responses to negative emotional stimuli: 1) when they were viewed without intentional regulation; and 2) during downregulation using cognitive reappraisal. Thirdly, I investigated whether self-esteem predicted reappraisal success. Method Twenty-nine healthy adults (age M=47, SD=15; 16 female) performed a cognitive reappraisal emotion regulation task during fMRI scanning. Participants viewed and subsequently reappraised or attended to negative and neutral images. Trait self-esteem (Rosenberg Self-Esteem Scale) was included as a predictor in a whole-brain multiple regression analysis. Analyses were thresholded at p<.005, k>p20, p<.05 family-wise error (FWE)-corrected at cluster-level. The anterior cingulate cortex (ACC; BA32) and the dorsal prefrontal cortex (PFC; BA6) were a priori regions of interest (ROI), since both have previously been reported in fMRI studies of self-esteem and cognitive reappraisal. A post-hoc ROI analysis tested the correspondence of self-esteem-related ACC activation with findings from a meta-analysis of emotion regulation. Ratings of negative emotional intensity following reappraisal trials were subtracted from ratings following attend-negative trials to index reappraisal success. Results Self-esteem was associated with potentiated ACC ROI activation during viewing of negative, compared to neutral, images (MNI x, y, z = -6, 17, 38, k=43, punc=.001 at peak, pFWE=.368 at cluster-level). For reappraisal compared to attended negative images, self-esteem was positively associated with activation in the left posterior insula (MNI x, y, z = -30, -10, 17, k=30, punc<.001 at peak, pFWE=.959 at cluster-level) and negatively associated with activation in the mid cingulate cortex (MNI x, y, z = 3, -34, 35, k=50, punc=.001 at peak, pFWE=.805 at clusterlevel). However, only the post-hoc ACC ROI analysis was significant after multiple comparison correction (MNI x, y, z = -6, 23, 38, k=22, punc=.001 at peak, pFWE=.021 at clusterlevel). For reappraisal, self-esteem was not related to activation in the ACC or dorsal PFC ROIs. Trait self-esteem did not correlate with reappraisal success, r =.16, p =.208. Conclusion Trait self-esteem may affect recruitment of the ACC during initial emotional appraisal. This may reflect successful automatic emotion regulation for high self-esteem, consistent with the demonstrated spatial overlap with a meta-analytic emotion regulation cluster. While selfesteem may affect brain responsivity during cognitive reappraisal, the observed trends must be interpreted carefully, since the findings do not survive correction for multiple comparisons, and emotional outcomes of applying reappraisal do not differ as a function of self-esteem. Taken together, these findings suggest that high trait self-esteem may be advantageous for rapid automatic emotion regulation, but not deliberate cognitive reappraisal.
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    An investigation of a neuro-inflammatory profile of HIV-associated neurocognitive disorders
    (2021) Williams, Monray Edward; Naude, Pieter; Joska, John; Stein, Dan
    Background HIV-associated neurocognitive disorder (HAND) is the consequence of the effects of HIV-1 within the central nervous system (CNS). HIV-associated neurocognitive impairment differs in severity with milder forms presenting in 50% of people living with HIV (PLWH), regardless of treatment status. Chronic immune dysregulation has been associated with HAND; in particular, it has been noted that inflammation persists despite the successful treatment with antiretroviral therapy (ART). However, the nature to which (neuro)inflammation influences cognitive performance and brain integrity remain unclear. Further, it is not clear how sequence variation in neurotoxic viral proteins, including Tat, affects inflammation in PLWH. This study aimed to 1) perform a systematic review of the existing literature to identify changes in peripheral immune markers that are associated with HAND in ART-experienced PLWH, 2) determine the association of blood peripheral immune markers with domain-based neurocognitive performance and structural brain changes in South African PLWH, and 3) lastly, to evaluate the possible influence of Tat sequence variation on a dysregulated immune profile in HIV-1C infection (i.e. Tat-C). Methods A systematic review of the published literature was performed to identify the most common markers associated with HAND in the ART-era. A panel of markers was measured in a treatment naïve South African cohort by enzyme-linked immunosorbent assays (ELISA). Cognitive performance was established using a battery of tests sensitive to HIV-associated neurocognitive impairment, with domain based scores utilized in analysis. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3T. Markers were correlated with neurocognitive performance and cortical thickness and surface area. Further, a prospective review of the literature was performed to determine the association between Tat sequence variation and underlying mechanisms (and inflammation) of HAND. The HIV-1 was genotyped and the influence of Tat sequence variation on immune marker levels was evaluated in a subset of South African participants. Results A systematic review of the existing literature suggested that peripheral immune markers of monocyte activation (sCD14 and sCD163) and inflammation (IL-18 and IP10) were associated with HAND in the majority of studies. Evaluation of blood immune markers in a treatment naïve South African cohort showed that thymidine phosphorylase (TYMP) and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher, while matrix metalloproteinase (MMP)9 levels were significantly lower in PLWH. The results further showed that in PLWH, worse psychomotor processing speed was associated with higher TYMP and NGAL levels and worse motor function was associated with higher NGAL levels. Further, in imaging analysis, it was reported that higher NGAL levels were associated with the reduced thickness of the bilateral orbitofrontal cortex. The association of NGAL withworse motor function was mediated by the cortical thickness of the bilateral orbitofrontal cortex. The associations between higher NGAL and TYMP levels with cortical thickness were largely found in the regions of the frontal cortex. A review of the literature suggests that key protein signatures (C31S and R57S) present in the Tat protein from HIV-1 subtype C (Tat-C) infection may contribute to the lowered inflammation. Supporting this hypothesis, the results from this thesis showed that HIV-1C participants with the R57S mutation had lower peripheral TYMP levels. Conclusions Current literature supports the premise that chronic inflammation may be an important contributor to the development of the milder forms of HAND. For patients on ART, other strategies are required to address the ongoing peripheral inflammation, in addition to simply suppressing the viral load. In a South African context, TYMP and NGAL may be promising markers for their involvement in HAND. Patients were largely treatment-naïve; therefore, these markers may represent HIV related effects without the potential confounding effects of ART. Therefore, these findings may represent long-standing effects which might persist in treatment experienced participants. In HIV-1C infection, the level of certain inflammatory markers may be influenced by the R57S Tat protein signature. To our best knowledge, this is the first thesis to report the association of these markers with HAND. These immune markers need to be investigated for their potential role in the underlying mechanisms of HAND.
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    An investigation of amygdala and hippocampal subregions and their relation to ageing in anxiety and related disorders
    (2024) Ntwatwa, Ziphozihle; Ipser, Jonathan; Groenewold, Nynke; Stein, Dan; van Honk, Jack
    Background Obsessive-compulsive disorder (OCD) and social anxiety disorder (SAD) are debilitating disorders that are associated with (inconsistent) evidence of hippocampal and amygdala volumetric abnormalities. In addition, both OCD and SAD are associated with accentuated biological aging, as indexed by cellular and molecular markers. Nevertheless, little is known about brain aging in OCD and SAD, or the extent to which inconsistencies in hippocampal and amygdala volume findings in these disorders may be due to the differential effect of age on the subfields from which these structures are composed. Accordingly, this dissertation set out to characterise differences in hippocampal and amygdala subfield volumes between healthy controls (HCs) and participants with OCD and SAD in large-scale MRI datasets and relate these to whole and regional brain aging. Methods Hippocampal and amygdala subfield volumes and brain age estimates were derived from T1 weighted MRI images from the OCD Brain Imaging Consortium (De Wit et al., 2014) and the European and South African Research Network in Anxiety Disorders (Bas-Hoogendam et al., 2017). Subfield volumes were segmented using an automated segmentation algorithm from Freesurfer (v6.0). The brain age analysis was performed by using a previously trained machine learning algorithm that provides brain age estimates for the whole brain, as well as for regions of interest (occipital, frontal, temporal, parietal, cingulate, insula, or cerebellar–subcortical features) (Kaufmann et al., 2019). Differences in relative brain age (brain predicted age difference; brain-PAD) were calculated by subtracting chronological age from the predicted brain age. Between-group differences (diagnosis vs HCs) in volumetric and brain-PAD estimates were assessed using a mixed-effects (d) model adjusted for several covariates. Subgroup analyses were performed to determine the association of the main findings with clinical characteristics. Finally, unique associations between subfield volumes and whole brain age were estimated using partial correlation analysis. Results There was no evidence for a difference in subfield volumes between individuals with OCD and HCs. However, we found that psychotropic medication use was associated with significantly smaller hippocampal dentate gyrus (d=-0.26, pFDR=0.042), molecular layer (d=-0.29, pFDR=0.042) and larger lateral (d=0.23, pFDR=0.049) and basal (d=0.25, pFDR=0.049) amygdala subfields than HCs. Individuals with OCD without psychotropic medication use had significantly smaller hippocampal CA1 (d=-0.28, pFDR=0.016) compared to HCs. No association was found for symptom severity. In contrast to the findings for OCD, individuals with SAD demonstrated significantly smaller basal (d= 0.32, pFDR=0.022), accessory basal (d=-0.42, pFDR=0.005) and corticoamygdaloid transition area (d=0.37, pFDR=0.014) amygdala subfields overall compared to HCs, and larger hippocampal CA3 (d=0.34, pFDR=0.024), CA4 (d=0.44, pFDR= 0.007), dentate gyrus (d=0.35, pFDR= 0.022) and molecular layer (d=0.28, pFDR=0.033). In addition, individuals with SAD without comorbid anxiety disorder had smaller lateral amygdala and hippocampal amygdala transition area, compared to HCs. No association was found for psychotropic medication use and symptom severity. Individuals with OCD (n=375) had significantly higher whole brain-PAD (+1.6 years, pFDR=0.006, d=0.20) compared to HCs (n=335), but no differences were observed in the regional models. The effect on whole brain brain-PAD estimates was largely driven by psychotropic medication use as higher relative brain age was evident in individuals with OCD with psychotropic medication use (+2.98 years, d=0.38, p <0.001) compared to HCs, but not in individuals without psychotropic medication use (+0.57 years, d=0.07, p =0.374) compared to HCs. No association was found for symptom severity. Partial correlation analysis found a significant negative association between hippocampal and amygdala volume and whole brain PAD in the OCD group (R=-0.224, p=0.00001), but not in the HC group (R=0.081, p=0.138), specifically the lateral nucleus (R=-0.18), CAT(R=-0.13), hippocampal fimbria (R=0.17), and hippocampal fissure (R=0.17) were significant in OCD. Individuals with SAD (n=107) had significantly higher whole brain-PAD (+2.5 years, d=0.33, pFDR=0.010) compared to HCs (n=137), and significantly higher regional brain-PAD in the temporal (+3.80 years, d=0.37, pFDR=0.008,), parietal (+3.57 years, d=0.38, pFDR=0.008), occipital (+3.26 years, d = 0.33, pFDR=0.010), and frontal regions (+2.97 years, d=0.33, pFDR=0.010,) compared to HCs. Brain PAD was higher in SAD without comorbid anxiety disorder, without MDD, and without psychotropic medication use. No association was found for symptom severity. There was no partial correlation between subfields and brain age. Discussion & Conclusion The evidence presented in the thesis suggests that 1) differences in subfield volumes between OCD and HCs were influenced by psychotropic medication use, which is consistent with previous studies that suggest that psychotropic medication status is a strong confounder for subcortical brain volumes observed in OCD, 2) differences in subfield volumes between SAD and HCs were observed in the areas associated with sensory information processing and these differences were partially influenced by psychiatric comorbidity, 3) both OCD and SAD were associated with accentuated brain aging with differential patterns in the whole and regional brain, dependent on clinical characteristics, and 4) only OCD relative brain age was associated with subfield volumes. It is unclear whether our findings in OCD and SAD reflect an adaptive response or are a pre-existing risk factor to these disorders, or both. Future longitudinal analysis is required to investigate whether the observed differences in subfield volume and brain age remain over time.
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    Childhood trauma in adults with social anxiety disorder and panic disorder: a cross-national study
    (2010) Lochner, C; Seedat, S; Allgulander, C; Kidd, M; Stein, Dan; Gerdner, A
    Objectives: The influence of childhood trauma as a specific environmental factor on the development of adult psychopathology is far from being elucidated. As part of a collaborative project between research groups from South Africa (SA) and Sweden focusing on genetic and environmental factors contributing to anxiety disorders, this study specifically investigated rates of childhood trauma in South African and Swedish patients respectively, and whether, in the sample as a whole, different traumatic experiences in childhood are predictive of social anxiety (SAD) or panic disorder (PD) in adulthood. Method: Participants with SAD or PD (85 from SA, 135 from Sweden) completed the Childhood Trauma Questionnaire (CTQ). Logistic regression was performed with data from the two countries separately, and from the sample as a whole, with primary diagnoses as dependent variables, gender, age, and country as covariates, and the CTQ subscale totals as independent variables. The study also investigated the internal consistency (Cronbach alpha) of the CTQ subscales. Results: SA patients showed higher levels of childhood trauma than Swedish patients. When data from both countries were combined, SAD patients reported higher rates of childhood emotional abuse compared to those with PD. Moreover, emotional abuse in childhood was found to play a predictive role in SAD/PD in adulthood in the Swedish and the combined samples, and the same trend was found in the SA sample. The psychometric qualities of the CTQ subscales were adequate, with the exception of the physical neglect subscale. Conclusion: Our findings suggest that anxiety disorder patients may differ across countries in terms of childhood trauma. Certain forms of childhood abuse may contribute specific vulnerability to different types of psychopathology. Longitudinal studies should focus on the potential sequential development of SAD/PD among individuals with childhood emotional abuse.
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    Clinical profile and psychiatric comorbidity of treatment seeking individuals with pathological gambling in South Africa.
    (2013) Sinclair, Heidi; Stein, Dan; Wilson, Don
    Background: Pathological gambling is a prevalent and disabling mental illness, which is frequently associated with mood, anxiety, and substance use disorders. However, there is relatively little data on comorbidity in individuals with pathological gambling from low and middle income countries such as South- Africa. Method: The Mini-International Neuropsychiatric Interview (MINI) was used to assess the frequency of DSM-IV-TR disorders among 100 male and 100 female treatment-seeking individuals with pathological gambling in South-Africa. The Sheehan Disability Scales were used to assess functional impairment. Results: : In a South-African sample of individuals with pathological gambling, the most frequent current comorbid psychiatric disorders were major depressive disorder (28%), anxiety disorders (25.5%) and substance use disorders (10.5%). Almost half of the individuals had a lifetime diagnosis of major depressive disorder (46%). Female pathological gamblers were significantly more likely to be diagnosed with a comorbid major depressive disorder or generalised anxiety disorder than their male counterparts. Conclusions: Data from South-Africa are consistent with previously published data from high income countries. Psychiatric comorbidity is common among individuals with pathological gambling.
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    Comparing the accuracy of brief versus long depression screening instruments which have been validated in low and middle income countries: a systematic review
    (BioMed Central Ltd, 2012) Akena, Dickens; Joska, John; Obuku, Ekwaro; Amos, Taryn; Musisi, Seggane; Stein, Dan
    BACKGROUND: Given the high prevalence of depression in primary health care (PHC), the use of screening instruments has been recommended. Both brief and long depression screening instruments have been validated in low and middle income countries (LMIC), including within HIV care settings. However, it remains unknown whether the brief instruments validated in LMIC are as accurate as the long ones. METHODS: We conducted a search of PUBMED, the COCHRANE library, AIDSLINE, and PSYCH-Info from their inception up to July 2011, for studies that validated depression screening instruments in LMIC. Data were extracted into tables and analyzed using RevMan 5.0 and STATA 11.2 for the presence of heterogeneity. RESULTS: Nineteen studies met our inclusion criteria. The reported prevalence of depression in LMIC ranged from 11.1 to 53%. The area under curve (AUC) scores of the validated instruments ranged from 0.69-0.99. Brief as well as long screening instruments showed acceptable accuracy (AUC[greater than or equal to]0.7). Five of the 19 instruments were validated within HIV settings. There was statistically significant heterogeneity between the studies, and hence a meta-analysis could not be conducted to completion. Heterogeneity chi-squared = 189.23 (d.f. = 18) p<.001. CONCLUSION: Brief depression screening instruments in both general and HIV-PHC are as accurate as the long ones. Brief scales may have an edge over the longer instruments since they can be administered in a much shorter time. However, because the ultra brief scales do not include the whole spectrum of depression symptoms including suicide, their use should be followed by a detailed diagnostic interview.
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    DSM-5: a collection of psychiatrist views on the changes, controversies, and future directions
    (BioMed Central Ltd, 2013) Nemeroff, Charles; Weinberger, Daniel; Rutter, Michael; MacMillan, Harriet; Bryant, Richard; Wessely, Simon; Stein, Dan; Pariante, Carmine; Seemuller, Florian; Berk, Michael; Malhi, Gin; Preisig, Martin; Brune, Martin; Lysaker, Paul
    The recent release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the American Psychiatric Association has led to much debate. For this forum article, we asked BMC Medicine Editorial Board members who are experts in the field of psychiatry to discuss their personal views on how the changes in DSM-5 might affect clinical practice in their specific areas of psychiatric medicine. This article discusses the influence the DSM-5 may have on the diagnosis and treatment of autism, trauma-related and stressor-related disorders, obsessive-compulsive and related disorders, mood disorders (including major depression and bipolar disorders), and schizophrenia spectrum disorders.
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    The effectiveness of problem solving therapy in deprived South African communities: results from a pilot study
    (BioMed Central Ltd, 2011) van't Hof, Edith; Stein, Dan; Marks, Isaac; Tomlinson, Mark; Cuijpers, Pim
    BACKGROUND:The majority of South Africans with a DSM-IV diagnosis receive no treatment for their mental health problems. There is a move to simplify treatment for common mental disorders (CMDs) in order to ease access. Brief problem solving therapy (PST) might fill the treatment gap for CMD's in deprived communities in South Africa. This pilot study evaluates the feasibility, acceptability and effectiveness of this PST program for CMD's in deprived communities around Cape Town. METHODS: A Dutch problem solving program was adapted and translated into English, Xhosa and Afrikaans and thereafter implemented in townships around Cape Town. An initial attempt to recruit participants for online PST proved difficult, and so the program was adapted to a booklet format. Volunteers experiencing psychological distress were invited to participate in the either individually or group delivered 5-week during self-help program. To evaluate the effectiveness, psychological distress was administered through self-report questionnaires. After completion of the intervention participants also rated the program on various acceptability aspects. RESULTS: Of 103 participants, 73 completed 5 weeks of brief PST in a booklet/workshop format. There were significantly more dropouts in those who used the booklet individually than in the group. Psychological distress measured on the K-10 and SRQ fell significantly and the program was evaluated positively. CONCLUSIONS: The results suggest that brief problem solving in a booklet/workshop format may be an effective, feasible and acceptable short-term treatment for people with CMD's in deprived communities. In this setting, group delivery of PST had lower drop-out rates than individual delivery, and was more feasible and acceptable. Randomized controlled trials are needed to evaluate the effect of brief self-help PST more rigorously.
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    ETD: The genetics of cognition in Schizophrenia
    (2024) Wootton, Olivia; Stein, Dan; Dalvie Shareefa
    Background: Cognitive impairment is a well-documented feature of schizophrenia and a major determinant of functional outcomes. Cognitive function may be assessed by measuring mean performance measures on cognitive tasks or by measuring variability in performance across tasks or trials of a task that make up a cognitive test battery. Previous research has demonstrated that both cognitive ability and schizophrenia are highly heritable, and that there is a genetic contribution to cognitive impairment in schizophrenia. However, insights into the genetic determinants of cognitive function in schizophrenia remain limited. The overarching aim of the study is to extend current understanding of cognitive impairment in schizophrenia by using previously under-researched or novel metrics of cognitive performance. First, the significance of the phenotype, within-individual variability (WIV) in cognitive performance, was examined in a South African study of people living with schizophrenia. Second, data from the UK Biobank was used to investigate the common genetic determinants of WIV. Third, genetically informed factors corresponding to broad cognitive abilities were used to explore the overlap between the latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions. Methods: A narrative review of the key literature on the clinical, neural, and genetic correlates of WIV was conducted. Multivariable linear regression analyses were then used to assess the relationship between WIV in cognitive performance and selected demographic and clinical variables in 544 people with schizophrenia and 861 matched controls from a South African case-control study. To explore the common genetic basis of WIV, a genome-wide association study (GWAS) of reaction time variability, a measurement of across-task WIV, was conducted in 404,302 individuals from the UK Biobank, a large population-based cohort. Linkage disequilibrium score regression was used to assess the genetic correlations between reaction time variability and selected neuropsychiatric traits, including schizophrenia. Lastly, Genomic Structural Equation Modelling was applied to cognitive data from the UK Biobank to derive latent factors corresponding to broad dimensions of cognitive function. The overlap between the latent cognitive factors, schizophrenia, and schizophrenia symptom dimensions was explored using a variety of statistical approaches, including bivariate MiXeR, the conjunctional false discovery rate method, and polygenic risk score analysis. Results: On a phenotypic level, increased WIV in performance speed across cognitive tests was significantly associated with a diagnosis of schizophrenia, older age, a lower level of education, and a lower score on the global assessment of functioning scale. The GWAS of reaction time variability yielded 161 genome-wide significant single nucleotide polymorphisms distributed across 7 loci, implicating genes involved in synaptic function and neural development. Reaction time variability showed a significant genetic correlation with several traits, including a positive correlation with schizophrenia. Lastly, three latent factors (visuo-spatial, verbal analytic and decision/reaction time) underlying the genetic correlations between the UK Biobank cognitive tests were identified. There was evidence of substantial polygenic overlap between each cognitive factor and schizophrenia but despite the extensive overlap, most significant loci shared between each latent cognitive factor and schizophrenia showed unique patterns of association with the respective factor. Biological annotation of the shared loci implicated gene-sets related to neurodevelopment and neuronal function. Conclusions: The significant relationship between measurements of WIV in performance speed and schizophrenia as well as global functioning in the disorder supports the use of WIV as a measure of cognitive dysfunction in schizophrenia. This thesis demonstrates that reaction time variability is heritable, has a positive genetic correlation with schizophrenia, and that genes associated with reaction time variability have similar biological functions to those affected in schizophrenia. Lastly, substantial overlap in the common genetic influences of latent cognitive factors and schizophrenia was demonstrated. This research suggests that genes related to neurodevelopment and neuronal function underpin cognitive deficits in schizophrenia.
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    Evidence-based treatment for Depersonalisation-derealisation Disorder (DPRD)
    (BioMed Central Ltd, 2013) Somer, Eli; Amos-Williams, Taryn; Stein, Dan
    BACKGROUND: Depersonalisation-derealisation disorder (DPRD) is a distressing and impairing condition with a pathophysiology that is not well understood. Nevertheless, given the growing interest in its pathogenesis, and the publication of a number of treatment trials, a systematic review of randomised controlled pharmacotherapy and psychotherapy trials is timely. METHODS: A systematic search of articles on DPRD published from January 1980 to August 2012, using Cochrane methods, was conducted. All randomised controlled trials (RCTs) of pharmacotherapy, psychotherapy, somatic interventions and a blend of these modalities for the treatment of depersonalisation disorder were included in the review. Searches were carried out on multiple databases. The bibliographies of all identified trials were checked for additional studies and authors were contacted for published trials. No unpublished trials were found and no restrictions were placed on language and setting. Data extraction sheets were further designed to enter specified data from each trial and risk of bias information was identified. PRISMA guidelines were also followed to ensure that our methodology and reporting were comprehensive. Of the unique 1296 papers that were retrieved, four studies met the inclusion criteria and were reviewed. RESULTS: Four RCTs (all within the duration of 12 weeks or less) met study criteria and were included (180 participants; age range 18-65 years). The four RCTs included two lamotrigine studies, one fluoxetine study and one biofeedback study. Evidence for the treatment efficacy of lamotrigine was found in one study (Cambridge Dissociation Scale, CDC: p < 0.001) with no evidence of effect for lamotrigine in the second study (CDS: p = 0.61 or Present State Examination: p = 0.17). Fluoxetine and biofeedback were not more efficacious than the control condition, although there was a trend for fluoxetine to demonstrate greater efficacy in those with comorbid anxiety disorder. The four studies had 'low' or 'unclear' risk of bias. CONCLUSION: The limited data from randomised controlled trials on the pharmacotherapy and psychotherapy of DPRD demonstrates inconsistent evidence for the efficacy of lamotrigine, and no efficacy for other interventions. Additional research on this disorder is needed.
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    Explanatory models of mental disorders and treatment practices among traditional healers in Mpumalanga South Africa
    (2010) Sorsdahl, Katherine Rae; Flisher, Alan; Wilson, Z; Stein, Dan
    Objective: In many traditional belief systems in Africa, including South Africa, mental health problems may be attributed to the influence of ancestors or to bewitchment. Traditional healers are viewed as having the expertise to address these causes. However, there is limited information on their explanatory models and consequent treatment practices. The present study examines traditional healers’ explanatory models (EMs) and treatment practices for psychotic and non-psychotic mental illnesses.Method: 4 focus group discussions (8 healers in each group) and 18 in-depth interviews were conducted. Four vignettes were presented (schizophrenia, depression, panic and somatization) and traditional healers’ views on the nature of the problem, cause, consequence, treatment and patient expectations were elicited. Results: Traditional healers held multiple explanatory models for psychotic and non-psychotic disorders. Psychotic illnesses appear to be the main exemplar of mental illness and were treated with traditional medicine, while nonpsychotic illnesses were not viewed as a mental illness at all.Additionally, traditional healers do not only use herbs and substances solely from “traditional” sources but rather have incorporated into their treatment practices modern ingredients that are potentially toxic. Conclusion:Interventions aimed at increasing the mental health literacy of traditional healers are essential. In addition, investigations of the effectiveness of traditional healer treatment for psychiatric disorders should be conducted.
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    Final Year Medical Students' Experience of Bullying: A Study at the University of Cape Town
    (2020) Fakroodeen, Adam Abdul Kader; Stein, Dan
    Background: Medical bullying has been identified as a growing concern internationally, with multiple studies showing a high prevalence in medical students and residents However, several questions remain unanswered, including a) the prevalence of experienced bullying within our local, socioeconomic and ethnically diverse population, b) which population groups are most likely to bully medical students, c) significant demographic data which may impact on severity, frequency and type of bullying experienced, d) what is the correlation between severity, frequency and types of bullying with psychological distress in our local population. This study aims to 1) examine the association between bullying frequency and bullying types with demographic variables in this population, 2) to investigate the association of bullying severity, bullying frequency and psychological distress, and 3) to gather qualitative data on medical bullying in respondents Methods: The data for this research were collected from final year medical students. The questionnaire included the modified Quinne questionnaire assessing different types of bullying and related frequency, and the CORE-GP questionnaire assessing psychological distress. Descriptive statistics were used to analyse the quantitative data, and thematic analysis was used to assess the qualitative data. Results: There was a high prevalence of reported bullying (86.8%), with no significant differences of overall bullying across demographic variables. However, certain types of bullying were more commonly experienced by female and black students. Consultants and registrars were reported to bully students more frequently than nurses. Increased bullying frequency was significantly associated with higher levels of psychological distress. The main themes to emerge in the qualitative analysis were 1) Negative emotions relating to demographic bullying, 2)Systemised bullying within specific departments which according to the student are repetitive and expected, and 3) Feelings of academic pressure and fear associated to the bullying they have encountered Conclusion: This study suggests that the frequency of perceived bullying in South African medical students is consistent with rates reported in the literature. Bullying may follow the lines of medical hierarchies (with consultants being perceived as most likely to be the bully). Further, social disparities seem to be associated with increased bullying, with female and black students more often targeted. Specific interventions are needed to address bullying and associated psychological distress.
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    Genetic and epigenetic associations with child development and mental health in a South African birth cohort
    (2025) Moyakhe, Lihle; Koen, Nastassja; Stein, Dan; Dalvie, Shareefa
    Childhood developmental and mental disorders – including internalising and externalising symptoms – are prevalent in low- and middle-income countries (LMICs) such as South Africa. There is growing interest in the associations between polygenic risk scores (PRS), epigenetic age (EA) deviation, DNA methylation risk scores (MRS), and key neurodevelopmental disorders such as attention-deficit hyperactivity disorder (ADHD). However, most work has thus far been undertaken in high-income countries (HICs) with participants of European ancestry; and populations of African ancestry have been notably under-represented. The Drakenstein Child Health Study (DCHS), an ongoing South African birth cohort study, provides an opportunity to investigate the associations of PRS, EA deviation, and MRS, with childhood developmental and mental health outcomes, in an ancestrally diverse study population. This doctoral project aimed to investigate potential genetic and epigenetic associations with adverse developmental and mental outcomes in children. This aim was addressed via five objectives. First, a systematic review was undertaken to collate existing work (both in HICs and LMICs) on associations between PRS (the weighted sum of risk alleles) and developmental and mental health disorders in childhood and adolescence. A second systematic review focused on associations between EA deviation (relative to chronological age) and the outcomes of interest. Third, empirical analyses of DCHS data investigated the relationship between a PRS for ADHD, and child developmental outcomes, as well as internalising and externalising symptoms. Fourth, the relationship between gestational EA deviation at birth, and child developmental and mental health outcomes in the DCHS, was explored. Finally, the association between MRS (the weighted sum of methylation markers' beta values) at birth, and the outcomes of interest, was investigated. The systematic reviews adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and standard methods were used to collate and analyse the data. In the DCHS, a PRS for ADHD was generated (target n=958) using summary statistics from the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium (discovery n=17,666). Gestational EA deviation at birth and MRS were calculated using DCHS umbilical cord blood samples (n=275) and summary statistics from the Pregnancy and Childhood Epigenetics (PACE) consortium (n=2,477 for the MRS analyses). Child developmental outcomes (i.e. cognitive, language and motor development) were derived from the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), and child mental health outcomes (i.e. internalising and externalising symptoms) from the Child Behaviour Checklist (CBCL). Associations of interest were investigated using bivariate and multivariable linear and logistic regression models, controlling for relevant covariates (including sociodemographic characteristics, psychosocial risk factors, child anthropometric measures and genomic principal components). In the first systematic review (of 14 studies, with ~50,000 participants), significant associations between PRS for several mental health disorders and adverse developmental/mental health outcomes were found. For example, a high ADHD PRS was found to be associated with adverse outcomes in childhood and adolescence in 5 of the 14 included studies. Additionally, 4 studies described associations between PRS for bipolar disorder and impaired cognitive function, and poor executive functioning, in children and adolescents; and 2 studies highlighted associations between schizophrenia PRS and ADHD, as well as internalising and externalising symptoms in children. In the second systematic review (of 4 studies with N~700 participants), gestational EA acceleration was found to be significantly associated with internalising symptoms in children. The empirical analyses yielded no significant genetic or epigenetic associations with the developmental or mental health outcomes of interest in the DCHS children. However, trend-level associations were observed - in both the unadjusted and the adjusted models - between gestational EA deviation at birth and child externalising symptoms (at 42 months) in the DCHS (unadjusted β = −0.19, p = 0.072; adjusted β = -0.17, p= 0.10). While limited by sample size and lack of ancestry-matched summary statistics, this work nonetheless represents a novel exploration of the potential genetic and epigenetic underpinnings of developmental and mental disorders in South African children. In future, further studies – ideally with larger sample sizes, ancestry-matched summary statistics and longitudinal developmental phenotype data – would be warranted to expand on this preliminary work. Ultimately, such research may provide insight into the genetic and epigenetic risk factors of developmental and mental health outcomes in children; and may inform targeted early interventions for at-risk children – particularly in resource-limited settings such as South Africa.
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    Global mental health and neuroethics
    (BioMed Central Ltd, 2015) Stein, Dan; Giordano, James
    BACKGROUND: Global mental health is a relatively new field that has focused on disparities in mental health services across different settings, and on innovative ways to provide feasible, acceptable, and effective services in poorly-resourced settings. Neuroethics, too, is a relatively new field, lying at the intersection of bioethics and neuroscience; it has studied the implications of neuroscientific findings for age-old questions in philosophy, as well as questions about the ethics of novel neuroscientific methods and interventions.DISCUSSION:In this essay, we address a number of issues that lie at the intersection of these two fields: an emphasis on a naturalist and empirical position, a concern with both disease and wellness, the importance of human rights in neuropsychiatric care, and the value of social inclusion and patient empowerment.SUMMARY:These different disciplines share a number of perspectives, and future dialogue between the two should be encouraged.
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    Impact of childhood trauma on functionality and quality of life in HIV-infected women
    (BioMed Central Ltd, 2011) Troeman, Zyrhea; Spies, Georgina; Cherner, Mariana; Archibald, Sarah; Fennema-Notestine, Christine; Theilmann, Rebecca; Spottiswoode, Bruce; Stein, Dan; Seedat, Soraya
    BACKGROUND:While there are many published studies on HIV and functional limitations, there are few in the context of early abuse and its impact on functionality and Quality of Life (QoL) in HIV. METHODS: The present study focused on HIV in the context of childhood trauma and its impact on functionality and Quality of Life (QoL) by evaluating 85 HIV-positive (48 with childhood trauma and 37 without) and 52 HIV-negative (21 with childhood trauma and 31 without) South African women infected with Clade C HIV. QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), the Patient's Assessment of Own Functioning Inventory (PAOFI), the Activities of Daily Living (ADL) scale and the Sheehan Disability Scale (SDS). Furthermore, participants were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) and the Childhood Trauma Questionnaire (CTQ). RESULTS: Subjects had a mean age of 30.1 years. After controlling for age, level of education and CES-D scores, analysis of covariance (ANCOVA) demonstrated significant individual effects of HIV status and childhood trauma on self-reported QoL. No significant interactional effects were evident. Functional limitation was, however, negatively correlated with CD4 lymphocyte count. CONCLUSIONS: In assessing QoL in HIV-infected women, we were able to demonstrate the impact of childhood trauma on functional limitations in HIV.
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    Investigating neuroinflammation in schizophrenia: a proton magnetic resonance spectroscopy (1H-MRS) and cytokine study
    (2022) Burger, Antoinette; Stein, Dan; Howells, Fleur
    Introduction: There are similarities in the phenomenology and psychobiology of schizophrenia and methamphetamine psychosis, with evidence of alterations in glutamatergic function in both conditions, and of involvement of inflammatory pathways in schizophrenia and methamphetamine abuse. Few studies have directly compared glutamatergic and inflammatory metabolites in thalamo-cortical circuitry across schizophrenia and methamphetamine-induced psychosis or assessed the relationship between such metabolites and inflammatory markers in either disorder. This study aimed to 1) compare glutamatergic and neuroinflammatory metabolites in thalamo-cortical circuitry in schizophrenia and methamphetamine-induced psychosis, and 2) to investigate associations between glutamatergic metabolites, neuroinflammatory metabolites, and peripheral cytokine levels in both disorders. Methods: One hundred and sixteen participants were recruited – 44 with schizophrenia, 34 with methamphetamine-induced psychosis, and 38 healthy controls. All participants underwent a magnetic resonance imaging scan, which included magnetic resonance spectroscopy with voxels located in the anterior cingulate cortex (ACC) and left thalamus as well as a chemical-shift imaging 2-dimensional slice. Neurometabolites obtained included glutamatergic metabolites (glutamate (Glu), glutamine (Gln) and glutamate plus glutamine (Glx)) and neuroinflammatory metabolites (myo-inositol (mI), n-acetyl-aspartate (NAA), and n-acetyl aspartate plus n-acetyl-aspartyl glutamate (NAA+NAAG)). Absolute metabolite concentrations are reported. Serum cytokine concentrations were measured. For group differences, parametric data were analysed with one-way analysis of variance and nonparametric data analysed with Kruskal Wallis tests, followed by relevant post-hoc tests. Associations were determined using Spearman's rank-order coefficient. Significant associations were followed by comparison of correlations of independent samples. Results: There were no differences between neurometabolites in schizophrenia and healthy controls. The methamphetamine-induced psychotic disorder group had lower relative nacetyl-aspartate plus n-acetyl-aspartyl glutamate in left dorsolateral prefrontal cortex and left frontal white matter, compared to healthy controls. In schizophrenia, positive associations were found between absolute glutamatergic metabolites and absolute inflammatory metabolites in the anterior cingulate cortex (n-acetyl-aspartate with glutamate, lower n-acetylaspartate with n-acetyl-aspartyl glutamate plus glutamate, myo-inositol with glutamate, myoinositol with glutamate plush glutamine). Several positive relationships were found in mI between different brain areas of the thalamo-cortical circuitry in the methamphetamineinduced psychosis group. Conclusion: In schizophrenia, the associations between lower glutamatergic and lower neuroinflammatory metabolites suggest dysfunction in neuronal tissues in the glutamateglutamine cycle within the thalamo-cortical circuit. In methamphetamine-induced psychosis, lower NAA+NAAG/Cr+PCr in the left dorsolateral prefrontal cortex and left frontal white mattersuggest compromised neuronal integrity associated with chronic disease progression. Furthermore, in this group the associations of mI between brain areas in the thalamo-cortical 6 circuit suggest that neuroinflammatory pathways in this circuit are dysfunctional. Taken together, there may be important differences in the neurobiology of schizophrenia and methamphetamine-induced psychosis.
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    Investigation of the Shared Genetic Influences on Bipolar Disorder, Borderline Personality Disorder and Regional Brain Structures
    (2021) Campbell, Megan; Dalvie, Shareefa; Stein, Dan; Ramesar, Raj; Rockiki, Jaroslav
    Background: The heritabilities of bipolar disorder (BD) and borderline personality disorder (BPD) are 80% and 65%, respectively, indicating substantial genetic contributions to both disorders. BD and BPD are often comorbid, and both disorders have a polygenic architecture. These variants are thought to subtly affect multiple pathways, associated with structural brain abnormalities commonly observed in patients with BD and BPD. Brain regions have been shown to be highly heritable and under distinct genetic influences. However, the overlap in genetic risk between BD and BPD and altered brain regions, respectively, has not yet been determined. Aims and Objectives: The aim of this project was to determine whether genetic risk for BD and BPD overlaps with genetic risk for altered brain regions. Methods: Genome-wide association study (GWAS) summary statistics for BD (Ncases=20,352; Ncontrols= 31,358), BPD (Ncase=998; Ncontrol=1,545), eight subcortical brain volumes (nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus) and intracranial volume (ICV) (N=27,087), and cortical surface area and thickness (N=37,479) were obtained. Pleiotropy and concordance were assessed using SNP-Effect Concordance Analysis. Conditional false discovery rate (cFDR) was used to condition BD and BPD GWAS results on genetic variants that influence brain regions. Linkage Disequilibrium Score Regression was used to examine genome-wide correlations between BD, BPD and brain regions. Mendelian randomization was used to test for causal associations between BD, BPD and each brain region, respectively. Results: There was evidence of significant pleiotropy and positive concordance between BD and BPD (ppleiotropy=5x10-4; pconcordance=1x10-6, OR=1.29). Significant pleiotropy was observed between BD and the thickness of several cortical regions and two gyri, namely the lateral occipital (p=2.25x10-5), pars triangularis (p=1.1x10-4), rostral anterior cingulate regions (p=2.18x10-4) and post central (p=7.9x10-6) and supramarginal gyri (p=1.45x10-7). Significant positive concordance was noted between BPD and thickness of the lateral occipital region (p=3x10-4; OR=1.02). After conditioning BD onto BPD and each regional brain GWAS, 171 additional variants were significantly associated with BD (FDR<0.05). Three additional SNPs were significantly associated with BPD when conditioned on thickness of the lateral orbitofrontal, lingual, precentral and supramarginal regions. Discussion: The findings here of genetic overlap between BD, BPD and altered brain structure, while novel, are consistent with previous work. The cFDR analyses, highlight synapse and neurotransmitter regulation as a key underlying mechanism between BD and altered brain regions. Further fine-grained delineation of the role of the environment in these relationships and the inclusion of non-European populations are critical next steps, as they may provide insight into risk factors, new areas of treatment and aid in early detection of at risk individuals.
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    MIMS Handbook of Psychiatric Medication
    (Arena Holdings, 2022) Stein, Dan; Hoffman, Jacob; Kadenge, Betty; Stein, Dan; Hoffman, Jacob; Kadenge, Betty
    There is general agreement on the value of evidence-based medicine in general practice. And there is growing acknowledgement that the treatment of psychiatric disorders is an important component of primary care. This volume addresses the logical conclusion from these two premises; there is a need for an evidence-based approach to the use of psychiatric medications in general practice. While the evidence base of psychopharmacology grows annually, there are relatively few attempts to synthesise this literature for general practitioners. Lengthy and cumbersome guidelines are unlikely to be read, much less implemented. Our aim here was to synthesise the evidence in a readable and easy-to-use format, using pharmacotherapy algorithms. The current volume updates previous attempts to meet this aim. The approach here draws in part on our experience with Continuing Medical Education courses for general practitioners. To that extent, we are grateful to the many GPs who have attended these courses, and who have advised us on how to improve them. We are also grateful to our colleagues who have helped us with this teaching, and to those in the pharmaceutical industry who have supported such teaching over the years. It would perhaps be remiss if we did not end by emphasising that psychiatry is concerned not only about brain circuitry and neurotransmitters, but also about the patient-doctor relationship, and the broader intersections between society and the individual. Arguably, psychopharmacology is both a science and a humanity. We hope that the treatment algorithms provided here are implemented with good clinical judgement. To purchase a physical copy of the handbook and for access to CPD points, please visit subs.mims.co.za
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    Mindfulness based cognitive therapy improves frontal control in bipolar disorder: a pilot EEG study
    (BioMed Central Ltd, 2012) Howells, Fleur; Ives-Deliperi, Victoria; Horn, Neil; Stein, Dan
    BACKGROUND: Cognitive processing in Bipolar Disorder is characterized by a number of attentional abnormalities. Mindfulness Based Cognitive Therapy combines mindfulness meditation, a form of attentional training, along with aspects of cognitive therapy, and may improve attentional dysfunction in bipolar disorder patients. METHODS: 12 euthymic BD patients and 9 control participants underwent record of electroencephalography (EEG, band frequency analysis) during resting states (eyes open, eyes closed) and during the completion of a continuous performance task (A-X version, EEG event-related potential (ERP) wave component analysis). The individuals with BD completed an 8-week MBCT intervention and record of EEG was repeated. RESULTS: (1) Brain activity, individuals with BD showed significantly decreased theta band power, increased beta band power, and decreased theta/beta ratios during the resting state, eyes closed, for frontal and cingulate cortices. Post MBCT intervention improvement over the right frontal cortex was seen in the individuals with BD, as beta band power decreased. (2) Brain activation, individuals with BD showed a significant P300-like wave form over the frontal cortex during the cue. Post MBCT intervention the P300-like waveform was significantly attenuated over the frontal cortex. CONCLUSIONS: Individuals with BD show decreased attentional readiness and activation of non-relevant information processing during attentional processes. These data are the first that show, MBCT in BD improved attentional readiness, and attenuated activation of non-relevant information processing during attentional processes.
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    Negative attributions towards people with substance use disorders in South Africa: Variation across substances and by gender
    (Biomed Central Ltd, 2012) Sorsdahl, Katherine; Stein, Dan; Myers, Bronwyn
    BACKGROUND:Little research has examined attitudes towards people who use substances in low and middle income countries (LMIC). Therefore, the present study examined the attributions made by the general South African population about people who use substances and whether these attributions differ by the type of substance being used, the gender of the person using the substance, or the characteristics of the person making the attribution.METHOD:A convenience sample of 868 members of the general public was obtained through street-intercept methods. One of 8 vignettes portraying alcohol, cannabis, methamphetamine or heroin, with either a male or female as the protagonist was presented to each respondent. Respondents' attitudes towards the specific cases were investigated. RESULTS: Respondents held equally negative views of the presented substances, with the exception of the cannabis vignette which was considered significantly less "dangerous" than the alcohol vignette. Respondents were more likely to offer "help" to women who use alcohol, but more likely to suggest "coercion into treatment" for men. Individuals who scored higher on the ASSIST were more likely to hold negative attitudes towards substance users and black African respondents were more likely to offer help to individuals who use substances. CONCLUSION: The stigma associated with substance use in South Africa is high and not necessarily dependent on the drug of choice. However, a range of factors, including gender of the substance user, and ethnicity of the rater, may impact on stigma. Interventions designed to strengthen mental health literacy and gender-focused anti-stigma campaigns may have the potential to increase treatment seeking behaviour.