Dan J. Stein

University of Cape Town | UCT · Department of Psychiatry and Mental Health

Given that humans originated in Africa, it is likely that many seminal psychological observations and interventions originate in the continent. Relatively little attention has been paid, however, to more recent African contributions to the scientific fields of psychiatry and clinical psychology. This article notes that a number of major contributio...

Global mental health has emerged as an important specialty. It has drawn attention to the burden of mental illness and to the relative gap in mental health research and services around the world. Global mental health has raised the question of whether this gap is a developmental issue, a health issue, a human rights issue, or a combination of these...

Psychiatry raises a range of long-standing philosophical debates, with a classical position holding that mental disorders are natural kinds that require explanation using scientific laws, and a critical position arguing that mental disorders are social constructions that require understanding using hermeneutic approaches. I have proposed an integra...

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demog...

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta‐analyzed epigenome‐wide a...

Background Magnetic Resonance Imaging (MRI)-based imaging techniques are useful for assessing white matter (WM) structural and microstructural integrity in the context of infection and inflammation. The purpose of this scoping review was to assess the range of work on the use of WM neuroimaging approaches to understand the impact of congenital and...

Background: Acute traumatic stress symptoms may develop in people who have been exposed to a traumatic event. Although they are usually self-limiting in time, some people develop post-traumatic stress disorder (PTSD), a severe and debilitating condition. Pharmacological interventions have been proposed for acute symptoms to act as an indicated pre...

Background Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of D...

Background Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important follow...

Background Detailed, comprehensive, and timely reporting on population health by underlying causes of disability and premature death is crucial to understanding and responding to complex patterns of disease and injury burden over time and across age groups, sexes, and locations. The availability of disease burden estimates can promote evidence-base...

Background Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensiv...

Work at the intersection of philosophy and psychiatry has an extensive and influential history, and has received increased attention recently, with the emergence of professional associations and a growing literature. In this paper, we review key advances in work on philosophy and psychiatry, and their related clinical implications. First, in unders...

Background: Epigenetic age acceleration (EAA, i.e., higher EA relative to chronological age) may be linked to adverse mental health outcomes in children. Previously, EAA has been associated with advanced physical maturation and early pubertal development in adolescents. However, research on epigenomic changes and mental health outcomes in children...

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European anc...

Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylo...

Background: Prenatal indoor air pollution and maternal psychosocial factors have been associated with adverse psychopathology. We used environmental exposure mixture methodology to investigate joint effects of both exposure classes on child behavior trajectories. Methods: For 360 children from the South African Drakenstein Child Health Study, we cr...

Background The study aim was to determine whether associations of antenatal maternal anaemia with smaller corpus callosum, putamen, and caudate nucleus volumes previously described in children at age 2–3 years persist to age 6-7 years in the Drakenstein Child Health Study (DCHS). Methods This neuroimaging sub-study was nested within the DCHS, a So...

Introduction There are approximately 16 million children who are HIV-exposed and uninfected (CHEU) worldwide. Studies suggest that CHEU are at risk for developmental impairment in infancy, particularly in language domains. However, there is limited research examining neurocognitive function in CHEU older than 2 years, including important pre-school...

Genomic scientists have long been promised cheaper DNA sequencing, but deep whole genomes are still costly, especially when considered for large cohorts in population-level studies. More affordable options include microarrays + imputation, whole exome sequencing (WES), or low-pass whole genome sequencing (WGS) + imputation. WES + array + imputation...

Background. Depression and anxiety are among the most prevalent mental health issues experienced worldwide. However, whereas cross-cultural studies utilize psychometrically valid and reliable scales, fewer can meaningfully compare these conditions across different groups. To address this gap, the current study aimed to psychometrically assess the B...

Objectives: This study aimed to examine the psychometric properties of the P4 suicide screener in a multinational sample. The primary goal was to evaluate the reliability and validity of the scale and investigate its convergent validity by analyzing its correlation with depression, anxiety, and substance use. Study design: The study design is a cro...

Background Early life is a key period that determines long-term health. Lung development in childhood predicts lung function attained in adulthood and morbidity and mortality across the life course. We aimed to assess the effect of early-life lower respiratory tract infection (LRTI) and associated risk factors on lung development from birth to scho...

Background The three-item Sexual Distress Scale (SDS-3) has been frequently used to assess distress related to sexuality in public health surveys and research on sexual wellbeing. However, its psychometric properties and measurement invariance across cultural, gender and sexual subgroups have not yet been examined. This multinational study aimed to...

Background There is a growing population of children with in utero HIV exposure who are at risk of poor neurodevelopmental outcomes despite avoiding HIV infection. However, the underlying neurobiological pathways are not understood and neuroimaging studies are lacking. We aimed to investigate the cortical brain structure of children who are HIV-exp...

Background Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditio...

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 control...

Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants wit...

Background Mental health service providers are increasingly interested in patient perspectives. We examined rates and predictors of patient-reported satisfaction and perceived helpfulness in a cross-national general population survey of adults with 12-month DSM-IV disorders who saw a provider for help with their mental health. Methods Data were ob...

DNA methylation (DNAm) is a developmentally dynamic epigenetic process, yet we still know little about how epigenetic effects on health outcomes vary over time; whether DNAm alterations during certain periods of development are more informative than others; and whether epigenetic timing effects differ by outcome. To address these questions, we appl...

Objective The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross‐sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 he...

Studies examining the neurocognitive and circuit-based etiology of psychiatric illness are moving toward inclusive, global designs. A potential confounding effect of these associations is general intelligence; however, an internationally validated, harmonized intelligence quotient (IQ) measure is not available. We describe the procedures used to me...

Central nervous system involvement in HIV infection leads to neurobehavioural sequelae. Although apathy is a well-recognised symptom in adults living with HIV linked to alterations in brain structure, there is scarce research examining motivation in children living with HIV (CLWH). We used the Children’s Motivation Scale (CMS; normative mean = 50,...

Purpose of review Perinatal mental health research provides an important perspective on neurobehavioral development. Here, we aim to review the association of maternal perinatal health with offspring neurodevelopment, providing an update on (self-)regulation problems, hypothesized mechanistic pathways, progress and challenges, and implications for...

Background/Aims: The emerging concept of retinal age, a biomarker derived from retinal images, holds promise in estimating biological age. The retinal age gap (RAG) represents the difference between retinal age and chronological age which serves as an indicator of deviations from normal ageing. This scoping review aims to collate studies on retinal...

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD...

Background Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Meth...

The Kessler Psychological Distress Scale (K10) has been widely used to screen psychological distress across many countries. However, its performance has not been extensively studied in Africa. The present study sought to evaluate and compare measurement properties of the K10 across four African countries: Ethiopia, Kenya, Uganda, and South Africa....

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, an...

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, w...

Objective We analyzed adult ADHD symptoms in a cross-cultural context, including investigating the occurrence and potential correlates of adult ADHD and psychometric examination of the Adult ADHD Self-Report Scale (ASRS) Screener. Method Our analysis is based on a large-scale research project involving 42 countries (International Sex Survey, N=72,...

Background: The publication of South Africa's National Mental Health Policy Framework and Strategic Plan 2023-2030 and the proposed National Health Insurance (NHI) make it timely to review that state of mental health services in the country, and to emphasize the importance of prioritising mental health as a pivotal component of holistic healthcare....

Background The causal effects of gut microbiome and the development of posttraumatic stress disorder (PTSD) are still unknown. This study aimed to clarify their potential causal association using mendelian randomization (MR). Methods The summary-level statistics for gut microbiome were retrieved from a genome-wide association study (GWAS) of the M...

Background: Social anxiety disorder (SAD) has been associated with alterations in amygdala and hippocampal volume but there is mixed evidence for the direction of volumetric alterations. Additionally, little is known about the involvement distinct subfields of these regions in the pathophysiology of SAD. Methods: T1-weighted MRI images from a large...

Prenatal alcohol exposure (PAE) can affect brain development in early life, but few studies have investigated the effects of PAE on trajectories of white matter tract maturation in young children. Here we used diffusion weighted imaging (DWI) repeated over three time points, to measure the effects of PAE on patterns of white matter microstructural...

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges...

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment‐resistant anxiety disorders (TR‐AD) informing such trials is currently lacking. We used a Delphi...

Background and aims: The ICD-11 chapter on mental, behavioral and neurodevelopmental disorders contains new controversial diagnoses including compulsive sexual behavior disorder (CSBD), intermittent explosive disorder (IED) and gaming disorder. Using a vignette-based methodology, this field study examined the ability of mental health professionals...

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitat...

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Con...

Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we buil...

Neuroanatomical findings on youth anxiety disorders are notoriously difficult to replicate, small in effect size and have limited clinical relevance. These concerns have prompted a paradigm shift toward highly powered (that is, big data) individual-level inferences, which are data driven, transdiagnostic and neurobiologically informed. Here we buil...

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164...

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (...

Background and aims: Problematic pornography use (PPU) is a common manifestation of the newly introduced Compulsive Sexual Behavior Disorder diagnosis in the 11th edition of the International Statistical Classification of Diseases and Related Health Problems. Although cultural, gender- and sexual orientation-related differences in sexual behaviors...

Objective People with psychotic disorders often experience neurocognitive deficits, such as neurocognitive impairment (NCI), which can negatively affect their daily activities (e.g., performing independent tasks) and recovery. Because of this, the American Psychology Association advocates integrating neurocognitive testing into routine care for peo...

Introduction There are growing concerns about commonly inflated effect sizes in small neuroimaging studies, yet no study has addressed recalibrating effect size estimates for small samples. To tackle this issue, we propose a hierarchical Bayesian model to adjust the magnitude of single-study effect sizes while incorporating a tailored estimation of...

Obsessive-compulsive disorder (OCD) is a chronic and debilitating psychiatric disorder that affects approximately 2–3% of the population globally. Studying spontaneous OCD-like behaviors in non-human primates may improve our understanding of the disorder. In large rhesus monkey colonies, we found 10 monkeys spontaneously exhibiting persistent seque...

Introduction Lifestyle factors such as smoking, alcohol use, suboptimal diet, and inadequate physical activity have been associated with increased risk of cardiovascular diseases. There are limited data on these risk factors among patients with psychosis in low- and middle-income countries. Objectives This study aimed to establish the prevalence o...

Background The corpus callosum (CC) is a brain structure with a high heritability and a potential role in psychiatric and substance use traits. However, the genetic relationship of the CC, and its subregions, with psychiatric phenotypes remains largely unclear. We aimed to investigate the genetic architecture of the CC and its subregions and its ov...

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensional...

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental tr...

Background Early detection of psychosis improves treatment outcomes, but there is limited research evaluating the validity of psychosis screening instruments, particularly in low-resourced countries. Aim This study aims to assess the construct validity and psychometric properties of the psychosis screening questionnaire (PSQ) in South Africa. Set...

Background Early studies identified sensory phenomena as an important facet of hair pulling and skin picking. Research in this area has grown in recent years; however, extant research on sensory abnormalities in BFRBs demonstrates limitations. The current study seeks to address gaps in the literature by examining differences in the experiences of s...

Cognitive impairment is a major determinant of functional outcomes in schizophrenia, and efforts to understand the biological basis of cognitive dysfunction in the disorder are ongoing. Previous studies have suggested genetic overlap between global cognitive ability and schizophrenia, but further work is needed to delineate the shared genetic archi...

Background Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non‐motor functioning remain to be elucidated. Objective To quantify cross‐sectional regional cerebellar lobule volumes using three dimensional T1‐weighted anatomical brai...

Background Mental health problems are common and impairing among university students, yet only a minority of students with psychological disorders access treatment. Understanding barriers to treatment is integral to planning services, especially in resource constrained settings like South Africa (SA). Methods Data collected across 17 institutions...

The dawning of democracy in South Africa provided the opportunity for a broad range of new policies, including in health and mental health. The Mental Health Act of 2002 embodied much needed transformation in the sector. The Ekurhuleni Declaration of 2012 articulated a comprehensive and compelling vision for mental health. Nevertheless, shortly the...

Objective Evidence shows that dialogic book-sharing improves language development in young children in low-middle income countries (LMICs), particularly receptive and expressive language. It is unclear whether this intervention also boosts development of other neurocognitive and socio-emotional domains in children. Using a randomized controlled tri...

Importance Traumatic brain injury (TBI) is known to cause widespread neural disruption in the cerebrum. However, less is known about the association of TBI with cerebellar structure and how such changes may alter executive functioning. Objective To investigate alterations in subregional cerebellum volume and cerebral white matter microstructure af...

Background The ability of older persons to meet their basic needs (i.e. personal, financial and housing security), as well as to perform Activities of Daily Living (ADL), is crucial. It is unclear, however, whether such measures exist. This systematic review aimed to review English-language measures of the ability of older persons to meet their bas...

The 11th revision of the International Classification of Diseases (ICD-11) is now published and all countries of the world will be asked to implement it in practice. The ICD-11 has made significant revisions to the classification of mental health disorders, which have real-world implications for clinical practice. This volume provides a clear overv...

Objective The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls acros...

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a...

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of Eur...