Thesis (PhD)--Stellenbosch Univesity, 2011. / ENGLISH ABSTRACT: It is well established that South African women are disproportionately affected by HIV/AIDS and gender based violence. Research to date has provided evidence for neurocognitive decline in individuals infected with HIV/AIDS and in individuals who have experienced early life trauma. However, many gaps remain in our knowledge about the neurocognitive profile of HIV and childhood trauma in South African women. The present study focused on the neurocognitive effects of HIV infection and childhood trauma, both separately and in combination in South African women. The primary aim of the study was to assess neurocognitive functioning in HIV-positive and matched HIVnegative controls, with and without a history of childhood trauma. Moreover, the study sought to assess the synergistic relationship between HIV and childhood trauma in influencing neurocognitive outcomes, a relationship which has not yet been investigated. A neuropsychological battery sensitive to HIV-related impairments was administered to 83 HIV-positive and 47 matched HIV-negative women with histories of childhood trauma. A history of childhood trauma was assessed using the Childhood Trauma Questionnaire short form (CTQ-SF). Forty eight of the 83 HIV-positive women were exposed to childhood trauma. Among the control subjects, a total of twenty women were exposed to childhood trauma. Findings of the present study revealed neurocognitive deficits in memory and executive functions. Results demonstrated significant HIV effects in memory (HVLT-R learning and delay trials), and executive functions (Halstead Category test). Similarly, a trauma effect was evident in delayed recall (HVLT-R delay). Moreover, results revealed a significant interaction effect between HIV status and trauma status on the WAIS-III Symbol Search Task, a task of psychomotor speed. However, HIV-negative controls with a history of childhood trauma scored the highest on this task. Although this finding was unexpected, it may suggest that psychomotor speed may not be a sensitive or discriminating test of childhood trauma in healthy adults. The present study demonstrated evidence for HIV and trauma effects in the ability domains of learning and delayed recall and executive functions. Although the present study did not find evidence for a synergistic relationship between HIV and trauma, it did provide evidence for both HIV and trauma effects on neurocognition, a finding in keeping with previous studies. Future research should be prospective in nature and should better delineate the nature, severity, and temporal relationship of childhood trauma to neurocognitive outcomes, as well as the mediators and moderators of these outcomes. / AFRIKAANSE OPSOMMING: Dit is alombekend dat Suid-Afrikaanse vroue buite verhouding swaar deur MIV/vigs en geslagsgebaseerde geweld getref word. Navorsing tot dusver lewer bewyse van neurokognitiewe verswakking by individue met MIV/vigs sowel as individue wat vroeg in hulle lewe reeds trauma ervaar het. Tog is daar steeds vele gapings in ons kennis oor die neurokognitiewe profiel met betrekking tot MIV en kindertrauma onder Suid- Afrikaanse vroue. Hierdie studie konsentreer op die neurokognitiewe uitwerking van MIV-infeksie en kindertrauma, afsonderlik sowel as gesamentlik, op Suid-Afrikaanse vroue. Die hoofdoel van die studie was om neurokognitiewe funksionering by MIV-positiewe vroue te bepaal en dit met gepaste MIV-negatiewe kontrolepersone te vergelyk, met én sonder 'n geskiedenis van kindertrauma. Daarbenewens wou die studie die sinergistiese verwantskap tussen MIV en kindertrauma in hul impak op neurokognitiewe uitkomste bepaal – 'n verwantskap wat tot dusver nog nie ondersoek is nie. 'n Neurosielkundige toetsbattery wat gevoelig is vir MIV-verwante swakhede is onder 83 MIV-positiewe vroue en 47 gepaste MIV-negatiewe kontrolepersone met 'n geskiedenis van kindertrauma afgeneem. 'n Geskiedenis van kindertrauma is met behulp van die kort weergawe van die kindertraumavraelys (CTQ-SF) vasgestel. Agt-en-veertig van die 83 MIV-positiewe vroue is as kinders aan trauma blootgestel. Van die kontrolegroep het 20 vroue in hul kindertyd trauma beleef. Die studie het neurokognitiewe tekorte in korttermyngeheue én uitvoerende funksies aan die lig gebring. Die resultate het 'n beduidende MIV-verwante uitwerking op korttermyngeheue (hersiene Hopkins- verbale leer-en-vertragingstoets, oftewel HVLT-R) sowel as uitvoerende funksies (Halstead-kategorietoets) getoon. Eweneens het die studie op 'n duidelike traumaverwante uitwerking op herinneringsvermoë (HVLT-R-vertraging) gedui. Daarbenewens het die WAIS-II- (Wechsler-volwassene-intelligensieskaal) simboolsoekopdrag – 'n psigomotoriese spoedtoets – 'n beduidende wisselwerkingseffek tussen MIV-status en traumastatus getoon. Tog het MIV-negatiewe kontrolepersone met 'n geskiedenis van kindertrauma die beste in hierdie opdrag gevaar. Hoewel hierdie bevinding verrassend was, kan dit daarop dui dat psigomotoriese spoed dalk nie 'n gevoelige of diskriminerende toets van kindertrauma by gesonde volwassenes is nie. Die studie het bewys gelewer van MIV- en traumaverwante uitwerkings op korttermyngeheue en uitvoerende funksies. Hoewel die ondersoek nie bewyse van 'n sinergistiese verwantskap tussen MIV en trauma kon vind nie, het dit wél bevestig dat MIV en trauma neurokognitiewe werking beïnvloed – 'n bevinding wat in pas is met vorige studies. Toekomstige navorsing behoort ondersoekend te wees en die aard, felheid en tydgebondenheid van die verwantskap tussen kindertrauma en neurokognitiewe uitkomste, sowel as die mediator- en moderatorveranderlikes van hierdie uitkomste, beter te omskryf.

Thesis (PhD)--Stellenbosch University, 2008. / ENGLISH ABSTRACT: Investigations into the neurobiology of obsessive-compulsive disorder (OCD) have provided useful insights into this prevalent and disabling disorder in recent decades. Encouraging advances have also been made in the pharmacological treatment of OCD. This has improved the quality of life for many who typically endure chronic unremitting symptoms. Despite the widespread use of first-line agents selective for the serotonergic system in OCD, relatively little is known about the neurobiology of treatment response, the specific components of the serotonin system involved in symptom modulation, and the overlapping and distinct brain regions impacted by alternative treatment options. Despite the advance that selective serotonin re-uptake inhibitors have been, a significant proportion of patients still fail to respond adequately to these agents, and alternative pharmacological interventions are required. The use of dopamine antagonists, a strategy which until recently has had only limited supporting data, presents one such alternative. Little however, is known about which subsets of patients are most likely to respond to these agents. In this thesis, I will present a series of six studies that use pharmacological treatments and single photon emission computed tomography (SPECT) to make contributions to three primary areas in OCD namely; neurobiology, treatment and the intersection of the two. First, I address OCD neurobiology by examining the impact of OCD on resting brain function. I then examine the effects of pharmacological challenge of the serotonin 1B receptor using sumatriptan on regional cerebral blood flow (rCBF) and clinical symptomatology. Second, I examine the intersection of neurobiology and treatment as I explore the changes in rCBF in response to treatment with inositol, a precursor of the phosphoinositol second messenger system. I then examine the distinct and overlapping effects on rCBF of treatment for 12 weeks with the selective serotonin re-uptake inhibitor (SSRI) citalopram across anxiety disorders. Third, I address treatment of OCD by examining the efficacy of controlled augmentation of serotonin re-uptake inhibitors with quetiapine, a dopamine antagonist, in treatment refractory OCD. I then combine this data with a second similar dataset to derive a predictive model for treatment outcome with quetiapine augmentation of SRIs. I demonstrate that rCBF in OCD differs significantly from normal controls, is correlated with severity in frontal brain regions, and remains an important line of investigation for OCD pathophysiology that has yet to fully delineated. Pharmacological challenge of the 5HT1B autoreceptor with the selective agonist sumatriptan results in heterogeneous behavioural and regional brain perfusion changes in OCD. Attenuation of pre-frontal perfusion following 5HT1B agonist administration is in line with the effects of SRIs. This work suggests that direct or indirect effects of SRIs on the 5HT1B receptor may be involved in mediating a clinical response in OCD. In the section exploring the intersection of neurobiology and treatment, I show that changes in rCBF partially parallel treatment response to SSRIs across a range of anxiety disorders. These data suggest that a degree of overlap exists in the neurobiology of treatment response or indeed core neurobiology across different anxiety disorders. I then show that effective treatment with inositol in OCD results in rCBF changes that are partially in line with the effects of SRIs on brain perfusion. These data support suggestions that second messengers may form part of the common pathway of action for effective anti-obsessional compounds. In the study in which we augmented SRIs with quetiapine, no advantage over placebo was found. This data has, however, recently been combined with similar data in meta-analyses and demonstrated a benefit over placebo. Finally, we found that patients who have failed fewer SRI trials, have more severe illness, and clinical dimensions with a putative dopaminergic underpinning, may derive preferential benefit from serotonin/dopamine antagonist augmentation of SRIs. Through this series of clinical treatment and functional brain imaging studies in OCD, I have contributed to the neurobiological understanding of OCD, and its treatment in refractory populations. In addition I have explored the intersection of these two domains using novel as well as conventional treatment across other anxiety disorders. Treatment and pharmacological challenges used, either directly or indirectly impacted the monoamine systems serotonin and dopamine and advanced our understanding of their involvement in symptom generation. Future work should focus on the functional intersection of brain function, treatment response, and functional genetic polymorphisms within the monoamine systems of the brain. / AFRIKAANSE OPSOMMING: Ondersoek na die neurobiologie van obsessief-kompulsiewe steuring (OKS) het in die afgelope dekades sinvolle bydraes gelewer tot die begrip van hierdie algemene en verminkende steuring. Bemoedigende vordering is ook in die farmakologiese behandeling van OKS gemaak. Dit het tot ’n verbetering in kwalitiet van lewe van meeste pasiënte gelei wat normaalweg kronies en onophoudelike simptome moet verduur. Ten spyte van die uiteenlopende gebruik van eerste-linie behandeling wat spesifiek inwerk op die serotonien sisteem in OKS, is relatief min bekend oor die neurobiologie van respons op behandeling. So ook is min bekend oor; eerstens die spesifieke komponente van die serotonien sisteem wat betrokke is by simptoom modulasie, en tweedens die gedeeltelik samevallende en afsonderlike brein streke wat deur alternatiewe farmakologiese behandelings beïnvloed word. Ten spyte van die vooruitgang wat die selektiewe serotonien heropname inhibeerders tot gevolg gehad het, is daar nog altyd ‘n betekenisvolle proporsie van pasiënte wat nie voldoende respondeer op hierdie behandelings opsie nie. Dus word alternatiewe opsies benodig. Een so ‘n opsie is die klas dopamien reseptor blokkeerders wat tot onlangs min ondersteunende data gehad het. So ook, is min bekend oor die subgroepe van pasiënte wat die meeste voordeel uit hierdie alternatief sal trek. In hierdie proefskrif sal ek ‘n reeks van ses studies wat farmakologiese middels en enkel foton emissie rekenaar tomografie (EFERT) gebruik om ‘n bydra tot kennis in drie primêre areas van OKS te maak. By name; neurobiologie, behandeling, en die kruispunt van die twee. Eerstens spreek ek neurobiologie aan deur middel van ’n studie wat rustende brein bloed vloei (rBBV) in OKS ondersoek. Hierna ondersoek ek veranderings op rBBV en simptome na eenmalige toediening van ‘n serotonien 1B reseptor agonis, sumatriptan. Tweedens ondersoek ek die kruispunt van neurobiologie en behandeling deur die effek van behandeling met inositol, ‘n voorloper van die fosfoinositol tweedeboodskapper sisteem, op rBBV. Ek ondersoek dan die rBBV patroon van veranderinge in brein streke wat deur twaalf weke van behandeling met die selektiewe serotonien heropname inhibeerder citalopram in verskeie angversteurings bewerkstellig word. Laastens, spreek ek behandeling van OKS aan deur middel van ‘n gekontroleerde studie wat ondersoek instel na die effektiwiteit van die byvoeging van quetiapien, ‘n dopamien reseptor antagonis, tot serotonien heropname inhibeerders in behandelingsweerstandige OKS. Ek kombineer dan hierdie data met ’n soortgelyke datastel om ‘n model af te lei wat kliniese uitkoms vir hierdie behandelings opsie voorspel. Ek het gedemonstreer dat rBBV in OKS betekenisvol verskil van gesonde vergelykbare kontroles. Hierdie verskille het gekorreleer met ernstigheid van OKS in frontale brein streke. Dus bly hierdie tipe studies ’n belangrike rigting van ondersoek in OKS patofisiologie wat tot op hede nie tenvolle uitgewerk is nie. Eenmalige toediening van sumatriptan, het heterogene gedrags en rBBV veranderings in OKS tot gevolg gehad. Pre-frontale verhogings in rBBV voor behandeling is met 5HT1B sumatriptan toediening verminder, ’n effek wat in lyn staan met die effek van selektiewe serotonien heropname inhibeerders. Hierdie werk stel voor dat direkte of indirekte effekte van selektiewe serotonien heropname inhibeerders op die 5HT1B reseptore betrokke mag wees by die meganisme van behandelingsrespons in OKS. In die afdeling waarin ek die kruispunt van neurobiologie en behandeling ondersoek, demonstreer ek dat rBBV veranderings gedeeltelik oorvleuel met dié wat deur selektiewe serotonien heropname inhibeerders veroorsaak word in verskeie angsversteurings. Hierdie data stel voor dat oorvleueling in die neurbiologie van beide behandelingsrespons en kern neurobiologie van hierdie angversteurings ’n waarskynlikheid is. Ek wys ook dat effektiewe behandeling met inositol in OKS ook veranderings in rBBV bewerkstellig wat gedeeltelik in lyn staan met dié van die selektiewe serotonien heropname inhibeerders. Hierdie data ondersteun dus hipoteses van ‘n gemeenskaplike meganisme, wat tweede boodskapper sisteme insluit, wat in die behandelings respons van effektiewe anti-obsessionale middels betrokke is. Die finale deel van hierdie proefskrif handel oor behandeling van OKS. Ten spyte van die onvermoë om ‘n verskil tussen quetiapien en plasebo te demonstreer, het ons onlangs met hierdie data in ‘n reeks meta-analises wel ‘n voordeel vir hierdie intervensie getoon. Ten slote, het ons gevind dat (1) pasiënte wat minder kursusse selektiewe serotonien heropname inhibeerders gefaal het; (2) voor behandeling ‘n erger vorm van OKS gehad het, en (3) ook voordoen met simptoom dimensies wat oënskynlik ‘n dopaminerge basis het, die grootste waarskynlikheid toon om met quetiapien byvoeging tot selektiewe serotonien heropname inhibeerders te respondeer. Met hierdie reeks behandelings en funksionele breinbeeldings ondersoeke, lewer ek ‘n bydra tot die begrip van OKS. Spesifiek dra ek by tot die begrip van die neurobiologie, hantering van behandelingsweerstandige OKS asook die kruispunt van die twee. Farmakologiese middels wat ons óf eenmalig óf vir ‘n volle behandelingskursus toegedien het, het direkte of indirekte uitwerkings op die serotonien and dopamien sisteme gehad, en dus dra hierdie werk ook by tot kennis oor dié se betrokkenheid al dan nie in simptoom modulasie in OKS. Toekomstige werk in die area sal in die breë fokus op die kruispunt van breinfunksie, behandelingsrespons en funksionele genetiese polimorfismes van die monoamien sisteem.

Dissertation (PhD)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts (obsessions) and repetiti ve mental acts or behaviours (compulsions) . For many years, it was considered a rather uncommon condition, caused by unconscious conflict, and somewhat resistant to treatment. In recent decades, however, it has emerged that OCD is a highly prevalent disorder, mediated by particular neuroanatomical circuits (e.g. striatal pathways) and neurochemical systems (e.g. the serotonin system), and responsive to treatment with serotonin reuptake inhibitors (SRIs) . Nevertheless, many questions remain; about the specificity of neuroanatomical findings to OCD, about the role of the multiple serotonin (5-HT) receptor subtypes (e.g. 5-HT10)' and about the appropriate pharmacotherapy for patients resistent to SRI treatment? In a series of studies, 1) the neuroanatomy of OCD was assessed by means of magnetic resonance imaging and neuropsychological testing, 2) the neurochemistry of OCD was assessed by means of functional brain imaging after administration of a 5-HT10 agonist, and 3) the pharmacotherapy of OCD was explored in a series of treatment-refractory OCD and OCD spectrum disorder patients using SRI augmentation with a dopamine blocker. Although no significant difference was found in the volume of the caudate in women with OCD and controls, there was a significant correlation between caudate volume and neuropsychological dysfunction in patients, consistent with evidence of striatal involvement in OCD. Functional imaging demonstrated behavioural heterogeneity, but brain-behaviour correlations were positive, consistent with preclinical evidence of a role for the 5-HTlD receptor in the mediation of OCD. Finally, preliminary treatment findings with dopamine blocker augmentation of a SRI were promising, consistent with preclinical understandings of the interactions between the dopamine and serotonin systems. Although oeD is a complex disorder, a number of future research avenues hold promise for providing a thorough delineation of its pathogenesis. / AFRIKAANSE OPSOMMING: Obsessief-kompulsiewe steuring (OKS) word gekenmerk deur indringende gedagtes (obsessies) en herhalende gedagtes of gedrag (kompulsies). Vir baie jare is dit beskou as 'n redelik seldsame toestand wat veroorsaak word deur onbewustelike konflik, en wat in 'n mate teen behandeling weerstandig is. Meer onlangs het dit egter na vore getree as 'n toestand wat baie dikwels voorkom, wat deur spesifieke neuroanatomiese siklusse (bv. striatale bane) en neurochemiese sisteme (bv. die serotonien-sisteem) teweeg gebring word, en wat op behandeling met serotonien heropname inhibeerders (SHIs) reageer. Nogtans is daar steeds baie vrae; oor die spesifisiteit van neuroanatomiese bevindinge vir OKS, oor die rol van die veelvuldige serotonien (5-HT) reseptor subtipes (bv. 5- HT1D), en oor die toepaslike farmakoterapie vir pasiënte wat weerstandig is vir SHI behandeling. In' n reeks van navorsingstudies, is 1.) die neuroanatomie van OKS deur middel van magnetiese resonans beelding en neurosielkundige toetse ondersoek, 2. ) die neurochemie van OKS deur middel van funksionele breinbeelding na toediening van 'n 5-HT1D agonis bepaal, en 3.) die farmakoterapie van OKS in 'n reeks van behandelingsweerstandige OKS en OKS-spektrum steuring pasiënte - waar gebruik gemaak is van SHI aanvulling met 'n dopamien-blokker - ondersoek. Alhoewel daar geen beduidende verskil in die volume van die caudata in vroue met OKS en kontroles gevind is nie, was daar 'n beduidende korrelasie tussen die caudata volume en neurosielkundige wanfunksionering in pasiënte, in ooreenstemming met striatale betrokkenheid in OKS. Funksionele beelding het positief, in demonstreer, maar ooreenstemming met brein-gedrag pre-kliniese heterogeneïteit korrelasies was in gedrag bewyse vir 'n rol vir die 5-HT1D reseptor in die bemiddeling van OKS. Ten laaste, voorlopige behandelingsbevindinge oor dopamienblokker aanvulling van 'n SHI is belowend, in ooreenstemming met v

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: The etiology of anxiety disorders remains incompletely understood. Clear evidence for a genetic component has been proposed; however, there is also an increasing focus on environmental factors and the interaction between these and the genetic components that may mediate (anxiety) disorder pathogenesis. No single gene or genetic component has been explicitly identified as being involved in the development of anxiety disorders. This is most likely due to a number of reasons, which include, for example, the heterogeneity of anxiety disorders, the contribution of environmental factors and methodological limitations (e.g. small sample size) of research studies. Until now, genetic association studies usually focused on one particular psychiatric disorder at a time. However, with the difficulty in identifying susceptibility genes and/or loci in heterogeneous disorders like obsessive-compulsive disorder and other conditions in the anxiety spectrum, it is perhaps timely to consider multivariate genetics and epidemiological studies in a number of disorders sharing a core characteristic – such as anxiety. In addition to genetic underpinnings, a number of environmental variables have also been identified as risk factors for pathological anxiety, including adverse life events like childhood physical and sexual abuse. The hypothesis for this project is that a pre-existing genetic vulnerability (or genetic risk) interacts with the impact of adverse life events to result in the development of one or more anxiety disorder(s). Considering phenotypic overlap amongst the anxiety disorders, it is likely that diverse networks of genes and/ or interacting pathways are responsible for the phenotypic manifestations observed. Sprague Dawley rats exhibiting behaviours indicative of anxiety in the context of environmental stressors (maternal separation and restraint stress) were used as model for the identification of novel susceptibility genes for anxiety disorders in humans. The striatum has previously been implicated as a candidate in the brain architecture of anxiety pathogenicity, and is also a site exhibiting a high degree of synaptic plasticity. The synaptic plasticity pathway was investigated using the dorsal striatum of the rat brain and several genes were identified to be aberrantly expressed in “anxious” rats relative to controls (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 and Arc). In humans, it was found that the severity of early adversity was significantly and positively associated with the presence of an anxiety disorder in adulthood. When the human homologues of the susceptibility candidate genes that were identified using the animal model were screened in a human cohort of patients with obsessive-compulsive disorder (OCD), panic disorder (PD) or social anxiety disorder (SAD) (relative to controls), five single nucleotide polymorphisms (SNPs) were found to be significantly associated with these conditions. Four of these SNPs were also found to significantly interact with the severity of childhood trauma. Haplotype analysis of variants within the identified susceptibility candidates revealed novel haplotype associations, four of which are located in the MMP9 gene. Notably, this the first study to link these particular mutations in the MMP9 gene with anxiety disorders and this finding is consistent with previous work suggesting that MMP9 is involved in conditions like cardiovascular disease and cancer which have been associated with increased prevalence of anxiety disorders. In conclusion, this project yielded important findings pertaining to the etiology of anxiety disorders. The use of a combined anxiety disorders cohort (OCD, PD and SAD) may suggest that the associations found here may hold true for anxiety disorders in general and not only for a particular clinically delineated condition. Childhood trauma was confirmed as an increased susceptibility risk for anxiety disorders. Also, this research contributed several novel susceptibility genes (MMP9, EGR2, EGR4, NTF4, and ARC), five significant SNP associations, four significant SNP-environment interactions and five haplotype associations (within MMP9 and BDNF) as candidates for anxiety pathogenicity. The identified polymorphisms and haplotypes were demonstrated to be associated with susceptibility to anxiety disorders in a gene-environment correlation and gene-environment interaction. / AFRIKAANSE OPSOMMING: Die oorsake van angssteurings word steeds nie volledig verstaan nie. Daar is duidelike bewyse vir 'n genetiese komponent, maar daar is ook toenemende fokus op omgewingsfaktore en die interaksie tussen hierdie omgewingsfaktore en genetiese komponente by angssteurings. Geen enkele geen of genetiese komponent is al geïdentifiseer as diè wat betrokke is by die ontwikkeling van angssteurings nie. Dit is waarskynlik weens 'n aantal redes, wat byvoorbeeld, die heterogeneïteit van angssteurings, die bydrae van omgewingsfaktore en metodologiese beperkings (bv. klein steekproef) van die navorsingstudies, insluit. Verder het genetiese assosiasiestudies tot nou toe gewoonlik net op een spesifieke psigiatriese versteuring op 'n slag gefokus. Maar, gegewe die uitdaging om vatbaarheidsgene en / of loci in heterogene steurings soos obsessief – kompulsiewe steuring (OKV) en ander toestande op die angsspektrum te identifiseer, is dit tyd om genetiese en kliniese studies in ‘n aantal steurings - met ‘n oorvleuende kern-element soos angs -, gesamentlik te oorweeg. Bykomend tot die genetiese boustene, is ‘n aantal omgewingsveranderlikes soos traumatiese lewenservarings tydens die kinderjare as risikofaktore vir patologiese angs geidentifiseer. Die hipotese vir hierdie projek is dat daar 'n interaksie tussen genetiese kwesbaarheid (of genetiese risiko) en traumatiese lewensevarings is en dat dit tot die ontwikkeling van 'n / veelvoudige angssteuring(s) kan lei. Inaggenome die fenotipiese oorvleueling tussen die angssteurings, is dit waarskynlik dat diverse netwerke van gene en / of interaktiewe geen-paaie vir die manifestasie van hierdie toestande verantwoordelik is. Sprague Dawley-rotte met gedragswyses aanduidend van angs, in die konteks van omgewingstressore (d.i. skeiding van die ma-rot en bedwang-stres [restraint stress]), is as model gebruik vir die identifisering van nuwe vatbaarheidsgene vir angssteurings in mense. Die striatum is voorheen as ‘n kandidaat in die brein-argitektuur van patologiese angs voorgehou, en is ook ‘n plek met ‘n hoë mate van sinaptiese plastisiteit. Die sinaptiese plastisiteit is ondersoek deur te fokus op die dorsale striatum van die rotbrein en daar is verskeie gene gevind wat anders is in “angstige” rotte in vergelyking met kontroles (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 en Arc). In mense is daar gevind dat die ernstigheidsgraad van vroeë trauma beduidend en positief met die teenwoordigheid van ‘n angssteuring tydens volwassenheid verband hou. Toe die menslike ekwivalente van die vatbaarheidsgene wat met die dieremodel geïdentifiseer is in ‘n mens-kohort met obsessief-kompulsiewe steuring (OKS), panieksteuring (PS) en sosiale angssteuring (SAS) ondersoek is, is gevind dat daar 5 enkele nukleotied polimorfismes (ENPs) is wat met die toestande verband hou. Daar is ook gevind dat vier van hierdie ENPs beduidend verband hou met die ernstigheidsgraad van trauma tydens die kinderjare. Haplotipe analise van variante binne die geïdentifiseerde vatbaarheidsgene het op nuwe haplotipe assosiasies – waarvan 4 op die MMP9-geen geleë is – gedui. Hierdie is dus die eerste studie wat gevind het dat dié spesifieke mutasies van die MMP9-geen met angssteurings verband hou. Hierdie bevinding strook met vorige werk wat daarop dui dat die MMP9-geen by toestande soos kardiovaskulêre siekte en kanker wat ook met verhoogde voorkoms van angssteurings verband hou, betrokke is. Ter afsluiting kan ons sê dat hierdie projek belangrike bevindinge oor die oorsake van angssteurings gemaak het. Die gebruik van ‘n gekombineerde angssteurings-kohort (OKS. PS en SAS) kan moontlik suggereer dat die assosiasies wat ons hier gevind het, waar is vir alle angssteurings en nie net vir ‘n spesifieke afgebakende toestand nie. Traumatiese ervarings tydens die kinderjare is ook bevestig as ‘n risiko vir die ontwikkeling van angssteurings. Hierdie navorsing het ook verskeie nuwe vatbaarheidsgene (MMP9, EGR2, EGR4, NTF4, en ARC), 5 beduidende ENP assosiasies, 4 beduidende ENP-omgewings-interaksies en 5 haplotipe assosiasies (by MMP9 en BDNF) geïdentifiseer as moontlike kandidate wat ‘n rol speel by die ontstaan van patologiese angs. Daar is ook gevind dat die geïdentifiseerde polimorfismes en haplotipes met vatbaarheid vir angssteurings in ‘n geen-omgewing- korrelasie en geen-omgewing- interaksie verband hou. Stellenbosch University http://scholar.sun.ac.za

No abstract available. / Thesis (MMed.)-University of Natal, Durban, 1991.

Thesis (PhD (Psychiatry))--Stellenbosch University, 2008. / BACKGROUND: Schizophrenia is a heterogeneous illness resulting from complex gene-environment interplay. The majority of molecular genetic work done has involved Caucasian populations, with studies in these and Asian populations showing 2-32% of sufferers to have chromosomal aberrations. So far the discovery of a specific susceptibility mechanism or gene still eludes us, but the use of endophenotypes is advocated as a useful tool in this search. No cytogenetic studies of this nature have been reported in any African schizophrenia population. AIM: The aim of the study was to combine genotypic and phenotypic data, collected in a homogenous population in a structured manner, with the hope of characterising an endophenotype that could be used for more accurate identification of individuals with possible chromosomal abnormalities. METHODOLOGY: A structured clinical interview was conducted on 112 Xhosa schizophrenia patients. (Diagnostic Interview for Genetic Studies, including Schedules for the Assessment of Negative and Positive Symptoms.) Blood samples (karyotyping and/or FISH analysis) as well as urine samples (drug screening) were obtained and nine head and facial measurements were performed. Descriptive statistics were compiled with reference to demographic, clinical and morphological variables. Comparisons between mean differences for these variables were made.

Thesis (PhD (Psychiatry))--University of Stellenbosch, 2005. / Many gaps remain in our current state of knowledge about the epidemiology, phenomenology, neurobiology, and psychopharmacology of posttraumatic stress disorder (PTSD) in children and adolescents. Empirical evidence, particularly in non-Western settings, is sparse and there is little convergent understanding of the interrelationship of epidemiological factors, PTSD symptom expression, full and partial syndromes, disorders comorbid with PTSD, and pharmacotherapeutic interventions. Clinicians are faced with the difficult task of treating this often complicated and debilitating disorder in youth in the absence of data from well-controlled clinical trials. The studies detailed here are a point of departure for understanding the confluence that exists between epidemiological, phenomenological, and pharmacotherapeutic aspects of adolescent PTSD. Two studies were conducted to investigate the prevalence and effects of violence exposure and PTSD, clinical and functional correlates of full and partial syndromes, and associated gender differences in school and clinic samples, respectively. Two preliminary open-label trials assessed the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) in adolescents with at least moderate severity PTSD. The results indicate that (i) partial PTSD is a common nosological entity in adolescents, (ii) gender-related differences in PTSD, even if not manifest in differences in prevalence (i.e., in the rates of trauma exposure and full and partial PTSD), may well manifest in symptom expression (i.e., higher symptom burden in girls), associated morbidity, and functional impairment, and (iii) SSRIs may be effective in treating core PTSD symptoms in this age group. While not yet demonstrated, the partial subtype may have similar biological underpinnings to full PTSD in adolescents and may benefit from similar pharmacotherapeutic interventions. This is an area deserving of further investigation. Controlled SSRI data are needed to establish if these should be agents of choice for paediatric PTSD.

Thesis (PhD)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: HIV infection, substance abuse, and psychiatric disorders are major public health issues in South Africa. Psychiatric disorders and substance-use disorders together have a negative impact on the health outcomes of people living with HIV and AIDS (PLWHA), such as poor adherence to anti-retrovirals (ARVs), HIV disease progression, lower CD4 counts, vulnerability to opportunistic infections, high viral loads, possible drug resistance, and an earlier onset of death. The overall aim of this study was to investigate the relationship between substance abuse practices and the health status and health behaviour of patients attending HIV clinics in the Cape Metropole. The study used a cross-sectional study design for collecting data on hazardous or harmful use of alcohol and problematic drug use, demographic information and health status among patients attending eight HIV clinics in the Cape Metropole. A sub-sample of patients were assessed on the following domains: depression, psychological distress, psychopathology, post-traumatic stress disorder (PTSD), risky sexual behaviour, adherence to ARVs, levels of resilience, levels of social support and patient’s work, family and social functioning. Of the 608, 10% of consecutively selected patients completed an additional psychiatric diagnostic interview (Mini International Neuropsychiatric Interview). The main findings to emerge from this study are: 1. Patients reporting hazardous or harmful use of alcohol and/or drug use are significantly more likely to be non-adherent to ARVs and have lower CD4 counts than their non-substance abusing counterparts 2. Hazardous or harmful use of alcohol has a direct influence on CD4 count resulting in lower CD4 counts and participants being less likely to be on ARVs. 3. Hazardous or harmful use of alcohol has a direct relationship in predicting tuberculosis (TB). 4. Hazardous or harmful users of alcohol and/or problematic drug users are more likely to report psychological distress (anxiety and depression), depression and low levels of family support than their non-using counterparts. 5. Participants who met the criteria for major depression are significantly more likely to be non-adherent to ARVs. 6. Gender, depression, psychological distress, and PTSD were found to be significant determinants of hazardous or harmful use of alcohol. 7. Psychological distress (anxiety and depression) is significant in directly predicting ARV non-adherence. 8. Male participants and those who stopped taking their ARVs were more likely to have lower CD4 counts than female participants and those who did not stop. 9. PTSD was found to predict psychological distress indicating that participants who experienced trauma were more likely to suffer from psychological distress (anxiety and depression) compared to those who did not experience any PTSD. Participants with lower levels of family support were more likely to suffer from psychological distress than those with high levels of family support. / AFRIKAANSE OPSOMMING: MIV infeksie, dwelmmisbruik en geestesversteurings is groot gesondheidskwessies in Suid-Afrika. Geestesversteurings en dwelmmisbruik het gesamentlik 'n negatiewe uitwerking op die gesondheid van mense wat met MIV en VIGS saamleef (PLWHA), soos byvoorbeeld nie-nakoming in die gebruik van antiretrovirale (ARV’s), MIVsiekteverloop, laer CD4-tellings, vatbaarheid vir opportunistiese infeksies, hoë virale ladings, moontlike weerstand teen medikasie en 'n verkorte leeftyd. Die oorkoepelende doel van hierdie studie was om die verhouding tussen dwelmmisbruik en die gesondheidstatus en -gedrag van pasiënte wat MIV klinieke in die Kaapse Metropool besoek, te bestudeer. Die studie het 'n deursnee-ontwerp gebruik om data in te samel oor die nadelige en gevaarlike gebruik van alkohol en problematiese dwelmgebruik, demografiese inligting, en die gesondheidstatus onder pasiënte wat agt MIV klinieke in die Kaapse Metropool besoek het. 'n Subgroep pasiënte geassesseer op die volgende gebiede: depressie, psigologiese angsversteuring, psigopatologie, posttraumatiese stresversteuring (PTSV), riskante seksuele gedrag, nakoming in die gebruik van ARV’s, weerstandigheidsvlakke , vlakke van sosiale ondersteuning, asook pasiënte se werk, familie en sosiale funksionering. Van die 608 deelnemers is 10% van die pasiënte opeenvolgend geselekteer om 'n addisionele diagnostiese psigiatriese onderhoud te ondergaan (Mini International Neuropsychiatric Interview). Die vernaamste bevindinge wat uit die studie gekom het, is: 1. Pasiënte wat nadelige en gevaarlike gebruik van alkohol en/of dwelms rapporteer is beduidend meer geneig om nie die gebruik van ARV’s na te kom nie, en het laer CD4-tellings as hulle eweknieë wat nie dwelms misbruik nie. 2. Die nadelige en gevaarlike gebruik van alkohol het 'n direkte invloed op CD4- tellings wat lei tot laer CD4-tellings en dat pasiënte minder geneig is om op ARV’s te wees. 3. Die nadelige en gevaarlike gebruik van alkohol hou direk verband met die voorspelbaarheid van tuberkulose (TB). 4. Nadelige en gevaarlike gebruikers van alkohol en/of problematiese dwelmgebruikers, is meer geneig om psigologiese angsversteurings (angs en depressie), depressie, en laer vlakke van familieondersteuning te rapporteer as hul niegebruiker-eweknieë. 5. Deelnemers wat aan die kriteria vir ernstige depressie voldoen, is aansienlik meer geneig tot nie-nakoming in die gebruik van ARV’s. 6. Daar is gevind dat geslag, depressie, psigologiese angs en PTSV beduidende bydraende faktore is tot die nadelige en gevaarlike gebruik van alkohol. 7. Psigologiese angsversteurings (angs en depressie) is beduidend om direk die nie-nakoming van ARV’s te voorspel. 8. Manlike deelnemers en diegene wat hul ARV’s gestaak het, was meer geneig om laer CD4-tellings te hê as vroulike deelnemers en diegene wat nie die gebruik van medikasie gestaak het nie. 9. Daar is gevind dat PTSV psigologiese angs voorspel het wat aandui dat deelnemers wat trauma ondervind het, meer geneig was om aan psigologiese angsversteurings (angs en depressie) te ly in vergelyking met diegene wat geen PTSV ervaar het nie. Deelnemers met laer vlakke van familieondersteuning was meer geneig om aan psigologiese angsversteurings te ly as diegene met hoë vlakke van familiebystand.