Doctoral Degrees (Psychiatry)

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Brain structural and white matter changes in first-episode schizophrenia and their demographic, clinical and cognitive correlates
(Stellenbosch : Stellenbosch University, 2018-03) Asmal, Laila; Emsley, Robin; Dazzan, Paola; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
ENGLISH SUMMARY : In schizophrenia, decreased brain volume and altered cortical thinning (especially in the frontal and temporal areas), as well as white matter deficits are described at the first-episode. The relationship between these brain measures and clinical symptoms, whether there is progression, and the extent to which antipsychotic medication contribute to or mitigate those changes remains unclear. The aim of this PhD was to examine cortical thickness, brain volume (cortical, subcortical, white matter) and diffusion tensor imaging data, looking at the relationship between these brain measures and clinical variables in the first year of schizophrenia treatment. This PhD focused on the MRI subcomponent of a larger prospective longitudinal study in first-episode schizophrenia (FES) patients treated with flupenthixol decanoate medication. The thesis integrates the findings of five journal manuscripts that each focused on a clinically relevant neuroimaging question that emerged as we assessed patients in the parent study, namely insight, childhood trauma, neuroimaging predictors of symptom expression, and antipsychotic related brain changes. In our first manuscript, baseline fractional anisotropy (FA) in a number of white matter tracts predicted poorer total insight in 89 FES patients, with a predilection for tracts associated with cortical midline structures. In our second manuscript, the ‘symptom misattribution’ domain of clinical insight was associated with significantly thinner left anterior cingulate and left rostral middle frontal cortices. Our studies address a need for research in larger samples in FES to better understand the neurobiology of insight in schizophrenia. In our third manuscript, baseline FA deficits in cortico-limbic circuitry was associated with childhood trauma in 53 FES patients compared to 51 controls, and there were differential effects of childhood emotional neglect (increased FA) and sexual abuse (decreased FA) on white matter in patients. To our knowledge, at the time of manuscript submission for publication, this was the first study examining the relationship between childhood trauma, FA and FES. For our fourth manuscript, baseline brain measures in 54 FES patients were differentially associated with state and trait symptom expression over 12 months, with global gray matter significantly associated with sensory integration and verbal learning trait scores, cortical volume with verbal learning trait scores, cortical thickness with social and occupational functioning trait scores, and white matter volume with motor coordination state scores. Of potential relevance to patient care is that these neuroimaging deficits at initial presentation in FES may predict enduring trait deficits in cognition, functioning and neurological soft signs. For our final manuscript, total antipsychotic dose was a predictor of substantial cortical brain volume reductions over twelve months of treatment in 23 antipsychotic naïve patients compared to 53 matched controls. Our finding of a significant relationship between antipsychotic dose and cortical volume reduction in this study strongly suggests causality. Future research directions stemming from this PhD include further exploration of our longitudinal data, strengthening our clinical assessments of insight and childhood trauma, connectomic analyses, a multi-modality neuroimaging approach, hippocampal subfield segmentation, and broadening our international collaborations.
The clinical course and outcomes of first episode psychosis : a study of the acute, medium and long-term outcomes in a cohort rigorously treated in the early phase of illness
(Stellenbosch : Stellenbosch University, 2022-04) Phahladira, Lebogang; Emsley, Robin; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
ENGLISH SUMMARY: The period surrounding the first episode of psychosis represents a critical period in the natural course of the illness. There are several studies on the nature of the clinical presentation, the effects of treatment, course, and the outcome of the illness. However, there remain several knowledge gaps. This PhD sought to address some of those gaps. The overall aim was to assess the acute, medium- and long-term clinical and functional outcomes of participants with first-episode schizophrenia spectrum disorders who received intensive treatment with a long-acting injectable antipsychotic over a period of 24 months. We reported a well-established finding that psychotic symptoms in patients with first-episode schizophrenia spectrum disorders respond well to antipsychotic treatment. Overall, outcomes were favourable, with 70% achieving symptom remission, 56% functional remission and 61% rating their quality of life as good or excellent (although only 29% met all three of our criteria for recovery simultaneously). Symptom remission may be an important stepping stone to recovery, insofar as very few patients (9%) who did not achieve symptom remission were able to achieve functional remission and a good subjective quality. Our finding on longitudinal assessment of changes in insight was that in contrast to clinicianrated insight, significant impairments in patient-rated insight persisted despite assured treatment. This suggests that insight impairment is more trait- than state-related. We found that depressive symptoms during the early phase of illness are intrinsic to psychosis and responded well to antipsychotic treatment. Regarding negative symptoms, we replicated the two-factor structure, namely an experiential and an expressive domain, although the two subdomains appear closely related rather than being independent entities. Premorbid correlates and treatment response trajectories were similar for the two subdomains. We found that secondary negative symptoms affect the subdomains differentially. Depression affects the experiential subdomain, whereas extrapyramidal symptoms affect the expressive subdomain. A link between lipid metabolism and negative symptoms is suggested in that post-hoc testing indicated that reductions in HDL-cholesterol levels were associated with less improvement in both expressive and experiential subdomain scores. Taken together, our findings support the use of long-acting injectable antipsychotics as a first line treatment in schizophrenia spectrum disorders, perhaps particularly in resource constrained settings such as our own.
Metabolic syndrome risk factor associations with clinical, functional and cognitive outcomes during the first year of treatment in schizophrenia spectrum disorders
(Stellenbosch : Stellenbosch University, 2021-03) Luckhoff, Hilmar Klaus; Emsley, Robin; Du Plessis, Stefan S.; Kilian, Sanja; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
ENGLISH SUMMARY : Treatment-emergent metabolic syndrome is an established risk factor for cardiovascular disease known to be associated with cognitive impairment, poor functioning and decreased quality of life in schizophrenia spectrum disorders. However, weight gain and increased lipids have also been correlated with clinical improvement in chronic schizophrenia patients. While most studies investigating the relationships between body mass and treatment outcome were conducted in patients treated with clozapine and olanzapine, it remains unclear to what extent the role of weight gain as a predictor of favourable clinical outcomes extends to include illness-specific symptom domains in first-episode patients treated with other antipsychotics with a lower obesogenic potential. The effects of other clinical (e.g. sex, substance use, baseline body mass) and treatment-related (e.g. antipsychotic dose, medication adherence) confounders on the above relationships is also unclear. In response to these knowledge gaps, the overarching aim of our doctoral studies was to explore the temporal evolution of metabolic syndrome risk factors and their effects on clinical outcome over 12 months of treatment in first-episode schizophrenia spectrum disorder patients. We found that an increase in body mass correlates with global psychopathology improvement as well as the disorganized symptoms domain of schizophrenia in first-episode patients (n=106) over 12 months of treatment, independent of the degree of antipsychotic exposure (sub-study I). The association between weight gain and clinical improvement extended to include better overall end-point cognition after 12 months of treatment in our first-episode patient cohort (n=72) (sub-study II). A differential effect for lower baseline body mass index as a predictor of end-point working memory performance was evident in substance users (unfavourable) compared to their non-using counterparts (favourable). The adverse role of low body mass index as an unfavourable prognostic marker was further substantiated by its associations with an earlier age of psychosis onset and more severe negative symptoms in first-episode patients (n=69) (sub-study III). The inclusion of a diffusion tensor imaging component to our research also revealed a similar differential association of body mass index with fronto-limbic white matter fractional anisotropy (FA) in first-episode patients (low body mass index, low FA) versus healthy controls (high body mass index, low FA) adjusting for age and sex (sub-study III). Extension of our structural neuroimaging research to include brain structures involved in the physiological, hedonic and cognitive control as part of a “core eating network” further identified smaller anterior hippocampal volumes as a sex-specific predictor of weight gain in first-episode patients (n=90) (sub-study IV). Our research supports the role of weight gain as a predictor of favourable clinical outcomes in first-episode schizophrenia patients for whom treatment adherence is assured. In contrast, low body mass and by extension failure to gain weight could represent an unfavourable prognostic marker in first-episode patients, particularly those who use substance users. Future studies would do well to combine clinical, biological and neuroimaging data in order to characterize intrinsic metabolic profiles in relation to long-term treatment outcomes in firstepisode schizophrenia.
A prospective study of clinical, biological and functional aspects of outcome in first episode psychosis
(Stellenbosch : Stellenbosch University, 2015-12) Chiliza, Bonginkosi; Emsley, Robin; Stellenbosch University. Faculty of Health Sciences. Dept. of Psychiatry.
ENGLISH ABSTRACT: Prospective, longitudinal clinical studies in first-episode schizophrenia have become relatively commonplace over the past two decades or more and have provided a wealth of useful information regarding the clinical presentation, treatment, course and outcome of the illness. However, there remain several unanswered questions. The majority of the studies have been conducted in upper income countries using often costly medication with heterogeneous samples. While the overall outcome of patients showed some progress, there is room for improvement yet. The overall aim of the dissertation was to study the clinical, biological and functional aspects of outcome in first episode schizophrenia in a resource constrained setting. We conducted a prospective, non-comparative, longitudinal study over 12 months assessing the efficacy and tolerability of a cost effective, long-acting injectable antipsychotic (LAI; flupenthixol decanoate) combined with an assertive monitoring program (AMP) among first-episode schizophrenia patients. Efficacy was measured by examining rates of response, remission and relapse, as well as quality of life and social and occupational functioning. Tolerability of our intervention was assessed by measuring extrapyramidal symptoms, and weight and metabolic changes. We also examined the evolution of treatment refractoriness by studying the rates of non-response, and other associated predictor and outcome features. We found high rates of acceptance and adherence to the LAI and AMP. Seventy percent of our patients completed the 12 months of treatment. Treatment response was achieved by 82% of the participants and 60% achieved remission. Although 19% of our patients relapsed, the majority of the relapses were mild and did not require hospitalisation. Patients experienced significant quality of life and social and occupational functioning improvements. We found mild rates of extrapyramidal effects, present in only a third of our cohort. The majority of the extrapyramidal effects were treated with anticholinergics or propranolol. Only 3% of our patients developed transient dyskinesia over the duration of the study. However, our cohort gained considerable weight, with statistically significant increases in BMI (p< .0001) and waist circumference (p=0.0006). Our cohort also experienced significant deleterious changes to their lipid profiles. Of particular concern was the increase in triglycerides (p=0.03) and a significant decrease in high density lipoprotein (p=0.005) leading to a 91% increase in the triglyceride/high density lipoprotein ratio. With regards to emerging treatment refractoriness, 12% of our patients met our pre-defined criteria for non-response. Non-responders were younger and at baseline showed more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS), and lower BMI. At endpoint the non-responders were characterised by higher levels of symptomatology in all domains; poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and a lower BMI. The strongest predictors of non-response were prominent baseline NSS and poor early (7 weeks) treatment response. In conclusion, the combination of an LAI with an AMP may be an effective and safe intervention in firstepisode schizophrenia, and may be particularly suitable for resource-constrained settings. The risk of weight gain and metabolic syndrome associated with antipsychotic treatment in first-episode schizophrenia are not restricted to second generation antipsychotics and low-potency first-generation antipsychotics. Ensuring effective treatment for first episode schizophrenia patients is a global problem, and likely to be under-recognised in LMICs.
A prospective study of neurological abnormalities in a cohort of Nigerian patients with schizophrenia
(Stellenbosch : Stellenbosch University, 2014-04) Ojagbemi, Abel Akinsola; Gureje, Oye; Emsley, Robin; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.
ENGLISH ABSTRACT: Background The changes in cognition, brain structure, and neurological soft signs which are characteristic of schizophrenia appear to have been present before the onset of the phenotype. They therefore find relevance as potential vulnerability markers of the disease. Neurological soft signs are of particular interest because they can be elicited quickly, reliably and cheaply. They have also been touted as markers of certain characteristics of schizophrenia. The most convincing evidence for these assertions come from prospective longitudinal studies of first episode, medication naive patients with schizophrenia. Most of these studies have been based on wholly Caucasian or mixed samples of Caucasians and other races. The present study provides important reference data on the nature of neurological soft signs in indigenous African subjects and clarifies the trait or state marking signs in this population. Method A total of 84 patients with first episode, schizophrenia, schizo-affective disorder, or schizophreniform disorder meeting criteria in the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders were consecutively recruited. Information on demographic characteristics, personal medical and psychiatric history, as well as family history was obtained at baseline. Neurological assessment was based on the 26 item Neurological Evaluation Scale. An exploratory factor analysis of the items in the scale was conducted using the baseline measurements. The derived sub-sets of neurological soft signs were then followed up longitudinally and in parallel with the ‘functional categories’ of the signs. The study describes the profile of neurological soft signs across the one year course of schizophrenia, as well as their relationship with a wide range of clinical and outcome variables. The severity of the baseline psychopathology was evaluated by administering the Positive and Negative Syndrome Scale. The overall clinical status was assessed using Clinical Global Impression. Additional assessments included the Calvary Depression Scale for Schizophrenia, Birchwood Insight Scale, Social and Occupational Functioning Assessment Scale, and the World Health Organisation Quality of Life Scale (WHO QoL-BREF). Pre-morbid adjustment was assessed using the Pre morbid Adjustment Scale, while extra-pyramidal effect of antipsychotics was assessed using the Extra-pyramidal Symptoms Rating Scale. Assessments were repeated at three monthly intervals for the full 12 months. Results Neurological soft signs were present in 96.4% of the sample at baseline. The signs loaded into a four factor structure: perceptual and motor sequencing (audio-visual integration, fist-edge palm, rhythm tapping, extinction, and right-left confusion), eye movements (synkinesis, convergence, and gaze impersistence), motor co-ordination and graphaesthesia (tandem walk, adventitious flow, and graphaesthesia), as well as stegreognosis. The scores for the perceptual and motor sequencing factor, as well as those for the sequencing of complex motor acts ‘functional category’ were stable across three measurements over 12 months (F=1.26, p=0.287, and F=1.87, p=0.158 respectively). The sequencing of complex motor act signs was not significantly correlated with the clinical and outcome characteristics of schizophrenia. However, other signs, as well as the NES total score were significantly correlated with more severe negative and disorganized psychopathology, as well as poorer outcome in terms of functioning and quality of life. Conclusion Neurological soft signs were present at a high frequency at baseline. A preponderance of the signs was associated with a more severe negative and disorganization psychopathology, as well as a poorer functional outcome and quality of life. Abnormal sequencing of complex motor act signs, and signs of abnormal cognitive processing of perceptual stimuli where resistant to changes in psychopathology, and thus may represent viable trait markers for schizophrenia in this cohort.

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Browsing Doctoral Degrees (Psychiatry) by browse.metadata.advisor "Emsley, Robin"

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