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 (MA)--Stellenbosch University, 2001 / ENGLISH ABSTRACT: Post-traumatic stress disorder (PTSD) is the most recognised mental disorder stemming from severe psychological trauma. One of the differential diagnoses of post-traumatic stress disorder, amongst others, is obsessive-compulsive disorder (OGD). These two disorders overlap at some point in terms of symptomatology. More specifically, both are characterized by recurrent intrusive thoughts. It has been hypothesized that trauma may also be a significant source of OGD development. OGD and PTSD are disorders that present in adulthood, as well as in childhood and adolescence. It is shown that PTSD and OGD can present comorbidly in adulthood and it is theorized that it may also be the case in childhood and adolescence. Evidence of OGD developing in the context of trauma and theories of how this might have happened are presented. It is shown how complicated it is to distinguish between OGD developing in the wake of trauma and PTSD and the importance of such a distinction. / AFRIKAANSE OPSOMMING: Post-traumatiese Stresversteurig (PTSD) is een van die mees erkende sielkundigeversteurings wat ontwikkel na die blootstelling aan sielkundige trauma. Obsessiewe-kompulsieweversteuring (OGD) is, onder andere, een van die differensiële diagnoses van PTSD. Die twee versteurings oorvleuel ten opsigte van simptomalogie. Meer spesifiek word beide gekenmerk deur herhalende indringende gedagtes. Daar word tans gehipotiseer dat trauma nie net 'n rol in die ontwikkeling van PTSD speel nie maar ook 'n oorsaaklike rol het in die ontwikkeling van OGD. OGD en PTSD is versteurings wat kan voorkom tydens volwassenheid, asook tydens die kinderjare en adolessensie. Daar word bewys gedoen van PTSD en OGD wat saam voorkom gedurende volwassenheid en daar word geteoretiseer dat dit ook die geval mag wees tydens die kinderjare en adolessensie. Bewys word gelewer van OGD wat ontwikkel na blootstelling aan trauma en teorië ten opsigte van die ontwikkeling word aangebied. Die onderskeid tussen OGD wat na trauma blootstelling ontwikkel en PTSD is ingewikkeld, dog is die onderskeid baie belangrik in vele opsigte.

Dissertation (PhD)--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: Obsessive-compulsive disorder is a severe, debilitating psychiatric disorder for which the underlying molecular aetiology still remains unclear. Evidence from family studies have suggested that OCD may be caused by a complex interplay of environmental and genetic factors. In order to identify the genetic factors that mediate OCD susceptibility, several genetic association studies have been undertaken, which have yielded inconsistent findings. Moreover, the majority of these studies have focused on a small number of candidate genes that encode components of the serotonin and dopamine neurotransmitter pathways. However, based on the complexity of clinical manifestations observed in OCD, it is likely that its pathogenesis is mediated by a broader complex of interrelated neurotransmitter systems and signal transduction pathways; consequently there is a need to identify and assess novel candidate genes. One method of identifying such novel OCD candidate genes is by utilising knowledge of diseases with phenomenological overlap with OCD, which lend themselves to better genetic dissection through linkage analysis and animal studies. Genetic loci for such disorders, identified though linkage analysis, could potentially harbour novel OCD candidate genes, while genes implicated through animal models may lead to the identification of additional susceptibility genes through delineation of pathways by, for instance, interactome analysis. One such disorder is schizophrenia, which manifests overlap in both symptoms and brain circuits with OCD. In schizophrenia, in addition to several case-control association studies having been performed, linkage data, studies of chromosomal aberrations and animal models have led to the identification of many chromosomal regions that may contain genes involved in its aetiology and thus may also contain OCD candidate genes. In the present investigation, this approach was employed using previously reported schizophrenia susceptibility loci to identify novel OCD candidate genes. All genes residing in each of these loci were catalogued and individually analysed using a battery of bioinformatic techniques in order to assess their potential candidature for OCD susceptibility. These analyses yielded 13 credible OCD candidate genes.Additional candidates were sought using information regarding a well-defined schizophrenia animal model, the heterozygous reeler mouse, that exhibits neurodevelopmental, neuroanatomical and behavioural abnormalities, similar to those displayed by patients with schizophrenia. The phenotype of these mice is caused by a mutation in Reln, which encodes reelin, a large extracellular matrix protein that plays a pivotal role in the ordered migration of neurons during the development of laminar brain structures. The fact that both reelin protein and mRNA levels have been shown to be reduced in post-mortem brain sections of schizophrenic patients, coupled with the observed behaviour and neurochemical similarities between the heterozygous reeler mouse and schizophrenic patients suggests that reelin may be involved in the pathogenesis of schizophrenia and hence also OCD. Furthermore, genes encoding proteins that interact with reelin may thus also be considered plausible candidate genes for both schizophrenia and OCD. For this reason, novel reelin-interacting proteins were sought using the N-terminal reeler-domain of reelin, a domain only found in proteins involved in neuronal migration, as “bait” in a yeast twohybrid screen of a foetal brain cDNA library. Putative reelin ligands were subsequently reevaluated using co-immunopreciptitation and mammalian two-hybrid analysis to corroborate the yeast two-hybrid findings. Results of these analyses showed that WDR47, a WD40-repeat domain protein, interacts with reelin via its reeler-domain; therefore, the gene encoding this ligand protein, as well as RELN itself, was also considered a credible OCD candidate gene. Each of the candidate genes identified using the afore-mentioned strategies were assessed for their potential role in the aetiology of OCD by case-control association studies of a cohort of Afrikaner OCD patients and control individuals. Statistically significant associations were detected for two genes, DLX6 and SYN3, with the disorder. These associations are exciting as they may point to novel mechanisms involved in OCD development. The identification of WDR47 as a novel reelin-interacting protein has significant implications for our understanding of reelin-dependant signalling. Using this protein as the starting point, further novel components of the reelin signalling pathway may be unravelled, an investigation which may lead to the identification of novel roles for reelin in neurodevelopment. Such novel components may, of course, also be considered OCD and schizophrenia candidate genes, which may, in turn, augment the existing knowledge of the pathophysiologies of OCD, schizophrenia and other neurodevelopmental disorders. Taken together, the current study yielded exciting results that warrants follow-up investigation in future. The identification of DLX6 and SYN3 as novel OCD susceptibility genes as well as the identification of WDR47 as a reelin-interacting protein may provide investigators with alternative avenues of research into potential pathological mechanisms involved both in OCD and schizophrenia, which may ultimately lead to alternative pharmacotherapy. / AFRIKAANSE OPSOMMING: Obsessiewe kompulsiewe steuring (OKS) is `n ernstige, verswakkende psigiatriese steuring waarvan die onderliggende molekulêre etiologie steeds onbekend is. Bewyse verkry vanuit familiestudies het voorgestel dat OKS moontlik veroorsaak word deur `n komplekse interaksie van omgewings en genetiese faktore. Om die genetiese faktore te identifiseer wat OKS vatbaarheid veroorsaak, is `n hele aantal genetiese assosiasie studies onderneem, wat teenstrydige resultate gelewer het. Wat meer is, die grootste hoeveelheid van hierdie studies het gefokus op `n klein aantal kandidaatgene wat vir komponente van die serotonien en dopamine neurotransmittor weë enkodeer. Dit is egter, gebaseer op die kompleksiteit van die kliniese manifestasies wat waargeneem word in OKS, heel moontlik dat die patogenisiteit van die siekte bemiddel word deur `n breër kompleks van interverwante neurotransmittor sisteme en seintransduksie weë. Daar is dus `n behoefte na die identifikasie en ondersoek van nuwe kandidaatgene. Een metode om sulke nuwe OKS kandidaatgene te identifiseer, is deur die gebruik van bestaande kennis oor siektes wat fenomenologiese ooreenkomste het met OKS, siektes wat makliker geneties ontleed kan word deur koppelingsanalises en dierestudies. Genetiese lokusse vir sulke versteurings, geïdentifiseer deur koppelingsanalises, het die potensiaal om nuwe OKS kandidaatgene in te sluit, terwyl gene wat geïmpliseer word deur dierestudies mag lei tot die identifisering van bykomende vatbaarheidsgene deur die ondersoek van weë deur, byvoorbeeld, interaktoom analises. `n Voorbeeld van so `n versteuring is skisofrenie, wat in manifestasie oorvleuel in beide simptome en breinstroombane met OKS. In skisofrenie het, addisioneel tot verskeie geval-kontrole assosiasiestudies wat gedoen is, koppelingsdata, studies van chromosomale afwykings en dierestudies gelei tot die identifikasie van verskeie chromosomale gebiede wat gene mag bevat wat betrokke kan wees in die etiologie van die siekte, en dus ook OKS kandidaatgene mag bevat. In die huidige ondersoek is hierdie benadering gevolg en is gebruik gemaak van voorheen gerapporteerde skisofrenie vatbaarheidslokusse om nuwe OKS kandidaatgene te identifiseer. Alle gene wat in hierdie lokusse voorkom is gekatalogiseer en individueel geanaliseer deur gebruik te maak van `n battery van bioinformatika tegnieke om hul potensiaal as kandidate vir OKS vatbaarheid te bepaal. Hierdie analise het 13 geloofwaardige OKS kandidate opgelewer. Addisionele kandidate is gesoek deur inligting van `n goed gedefinieerde skisofrenie dieremodel te gebruik, naamlik die heterosigotiese “reeler” muismodel, wat neuro-ontwikkelings-, neuroanatomiese- en gedragsabnormaliteite vertoon, soortgelyk aan dié wat voorkom by pasiënte met skisofrenie. Die feit dat daar aangetoon is dat beide reelin protein en bRNS vlakke verlaag is in post-mortem brein seksies van skisofrenie pasiënte, gekoppel aan die gedrags- en neurochemiese ooreenkomste wat gesien word tussen heterosigotiese “reeler” muise en skisofrenie pasiënte, stel voor dat reelin betrokke is by die patogenese van skisofrenie en dus ook OKS. Vir hierdie rede is nuwe proteïene gesoek wat `n interaksie met reelin toon, deur gebruik te maak van die N-terminale reeler-domein van reelin, `n domein wat slegs gevind word in proteïene wat betrokke is by neuronale migrasie, as “aas” in `n gis-twee-hibried sifting van `n fetale brein cDNS biblioteek. Vermeende reelin ligande is vervolgens herevalueer deur gebruik te maak van koimmunopresipitasie en soogdier twee-hibried analises om die gis-twee-hibried bevindings te bevestig. Resultate van hierdie analises het getoon dat daar interaksie is tussen WDR47, `n WD40-herhalingsdomein protein, met reelin via sy reeler-domein. Die geen wat hierdie ligand protein enkodeer, sowel as RELN self, is dus beskou as ‘n geloofwaardige OKS kandidaatgeen. Elkeen van die kandidaatgene wat geïdentifiseer is deur gebruik te maak van bogenoemde strategieë is ondersoek vir `n potensiële rol in die etiologie van OKS deur gebruik te maak van geval-kontrole assosiasie studies met `n groep Afrikaner OKVS pasiënte en kontrole individue. Statisties-betekenisvolle assosiasies met die versteuring is vasgestel vir twee gene, DLX6 en SYN3. Hierdie assosiasies is opwindend aangesien hul nuwe meganismes betrokke by OKS ontwikkeling mag aantoon. Die identifikasie van WDR47 as ‘n nuwe protein wat interaksie met reelin vertoon, het betekenisvolle implikasies vir die verstaan van reelin-afhanklike seining. Deur hierdie proteïn as die beginpunt te gebruik kan vêrdere nuwe komponente van die reelin seinweg ontdek word, `n ondersoek wat mag lei tot die identifisering van nuwe funksies vir reelin in neuro-ontwikkeling. Sulke nuwe komponente mag, natuurlik, ook in aanmerking kom as OKS en skisofrenie kandidaatgene, wat op sy beurt weer die bestaande kennis van die patofisiologie van OKS, skisofrenie en ander neuro-ontwikkelings versteurings mag verbreed. In samevatting, hierdie studie het opwindende resultate gelewer wat opvolgondersoeke in die toekoms regverdig. Die identifikasie van DLX6 en Syn3 as nuwe OKS vatbaarheidsgene, sowel as die identifisering van WDR47 as ‘n protein wat interaksie vertoon met reelin, mag aan navorsers alternatiewe navorsingsweë voorsien om die moontlike patologiese meganismes wat betrokke is by beide OKS en skisofrenie te ondersoek, wat uiteindelik mag lei tot alternatiewe farmakoterapie.

Apesar do transtorno obsessivo-compulsivo (TOC) ser um transtorno mental grave, que causa acentuado sofrimento e interferência na vida, ele ainda é subdiagnosticado na população. Além disso, a prevalência de TOC e sintomas obsessivo-compulsivos (SOC) e o impacto na qualidade de vida (QV) de adolescentes ainda não foram suficientemente estudados. A presente tese é composta por dois estudos: 1) um levantamento de base populacional para investigar a prevalência de SOC e TOC em adolescentes, comparando características demográficas e clínicas entre os sexos; 2) uma comparação entre adolescentes com e sem TOC quanto à QV e associação entre os domínios de QV e características clínicas. Nossos resultados apontam prevalência de 3,3% de TOC e 18,3% de SOC na amostra estudada, com meninas apresentando taxas mais elevadas em comparação aos meninos. No entanto, apesar dos altos índices, apenas um reduzido número de adolescentes já havia sido diagnosticado com TOC anteriormente à pesquisa (9,3%) e um percentual ainda menor recebia tratamento para a doença (6,7%). Além disso, quando comparados a adolescentes sem o transtorno, o grupo com TOC apresentou maiores prejuízos em todos os domínios de QV. Também, a presença de sintomas depressivos demonstrou estar associada com pior QV. Esses achados nos permitem concluir que, apesar da alta prevalência, o TOC é subdiagnosticado e ainda pouco tratado em adolescentes, porém, causa impacto significativo na QV dos jovens, contribuindo para prejuízos em todos os domínios. / Even though obsessive-compulsive disorder (OCD) is considered a severe mental illness, causing a high degree of suffering and significantly affecting patients’ lives, the disorder remains underdiagnosed in the general population. Moreover, the prevalence of OCD and obsessive-compulsive symptoms (OCS) and their impact on the quality of life of adolescents have not been extensively studied. The present dissertation comprises two studies, namely: 1) a population-based study designed to investigate the prevalence of OCS and OCD among adolescents, comparing demographic and clinical characteristics according to gender; and 2) a comparison between adolescents with and without OCD in relation to quality of life and the association between clinical characteristics and domain-specific quality of life impairment. Our results revealed a prevalence of 3.3% of OCD and 18.3% of OCS in the sample assessed, with girls presenting higher prevalence rates when compared with boys. Notwithstanding, despite the high rates observed, only a limited number of adolescents had been diagnosed with OCD before the study (9.3%), and an even smaller group was under treatment for the disorder (6.7%). In addition, when compared with adolescents without OCD, the group with the disorder showed poorer scores in all quality of life domains assessed. Also, the presence of depressive symptoms showed an association with poorer quality of life. These findings suggest that, in spite of the high prevalence of OCD, the disorder is still underdiagnosed and undertreated among adolescents. In addition, our findings confirm the significant impact of OCD on the quality of life of young patients, affecting all related domains.

Apesar do transtorno obsessivo-compulsivo (TOC) ser um transtorno mental grave, que causa acentuado sofrimento e interferência na vida, ele ainda é subdiagnosticado na população. Além disso, a prevalência de TOC e sintomas obsessivo-compulsivos (SOC) e o impacto na qualidade de vida (QV) de adolescentes ainda não foram suficientemente estudados. A presente tese é composta por dois estudos: 1) um levantamento de base populacional para investigar a prevalência de SOC e TOC em adolescentes, comparando características demográficas e clínicas entre os sexos; 2) uma comparação entre adolescentes com e sem TOC quanto à QV e associação entre os domínios de QV e características clínicas. Nossos resultados apontam prevalência de 3,3% de TOC e 18,3% de SOC na amostra estudada, com meninas apresentando taxas mais elevadas em comparação aos meninos. No entanto, apesar dos altos índices, apenas um reduzido número de adolescentes já havia sido diagnosticado com TOC anteriormente à pesquisa (9,3%) e um percentual ainda menor recebia tratamento para a doença (6,7%). Além disso, quando comparados a adolescentes sem o transtorno, o grupo com TOC apresentou maiores prejuízos em todos os domínios de QV. Também, a presença de sintomas depressivos demonstrou estar associada com pior QV. Esses achados nos permitem concluir que, apesar da alta prevalência, o TOC é subdiagnosticado e ainda pouco tratado em adolescentes, porém, causa impacto significativo na QV dos jovens, contribuindo para prejuízos em todos os domínios. / Even though obsessive-compulsive disorder (OCD) is considered a severe mental illness, causing a high degree of suffering and significantly affecting patients’ lives, the disorder remains underdiagnosed in the general population. Moreover, the prevalence of OCD and obsessive-compulsive symptoms (OCS) and their impact on the quality of life of adolescents have not been extensively studied. The present dissertation comprises two studies, namely: 1) a population-based study designed to investigate the prevalence of OCS and OCD among adolescents, comparing demographic and clinical characteristics according to gender; and 2) a comparison between adolescents with and without OCD in relation to quality of life and the association between clinical characteristics and domain-specific quality of life impairment. Our results revealed a prevalence of 3.3% of OCD and 18.3% of OCS in the sample assessed, with girls presenting higher prevalence rates when compared with boys. Notwithstanding, despite the high rates observed, only a limited number of adolescents had been diagnosed with OCD before the study (9.3%), and an even smaller group was under treatment for the disorder (6.7%). In addition, when compared with adolescents without OCD, the group with the disorder showed poorer scores in all quality of life domains assessed. Also, the presence of depressive symptoms showed an association with poorer quality of life. These findings suggest that, in spite of the high prevalence of OCD, the disorder is still underdiagnosed and undertreated among adolescents. In addition, our findings confirm the significant impact of OCD on the quality of life of young patients, affecting all related domains.

Apesar do transtorno obsessivo-compulsivo (TOC) ser um transtorno mental grave, que causa acentuado sofrimento e interferência na vida, ele ainda é subdiagnosticado na população. Além disso, a prevalência de TOC e sintomas obsessivo-compulsivos (SOC) e o impacto na qualidade de vida (QV) de adolescentes ainda não foram suficientemente estudados. A presente tese é composta por dois estudos: 1) um levantamento de base populacional para investigar a prevalência de SOC e TOC em adolescentes, comparando características demográficas e clínicas entre os sexos; 2) uma comparação entre adolescentes com e sem TOC quanto à QV e associação entre os domínios de QV e características clínicas. Nossos resultados apontam prevalência de 3,3% de TOC e 18,3% de SOC na amostra estudada, com meninas apresentando taxas mais elevadas em comparação aos meninos. No entanto, apesar dos altos índices, apenas um reduzido número de adolescentes já havia sido diagnosticado com TOC anteriormente à pesquisa (9,3%) e um percentual ainda menor recebia tratamento para a doença (6,7%). Além disso, quando comparados a adolescentes sem o transtorno, o grupo com TOC apresentou maiores prejuízos em todos os domínios de QV. Também, a presença de sintomas depressivos demonstrou estar associada com pior QV. Esses achados nos permitem concluir que, apesar da alta prevalência, o TOC é subdiagnosticado e ainda pouco tratado em adolescentes, porém, causa impacto significativo na QV dos jovens, contribuindo para prejuízos em todos os domínios. / Even though obsessive-compulsive disorder (OCD) is considered a severe mental illness, causing a high degree of suffering and significantly affecting patients’ lives, the disorder remains underdiagnosed in the general population. Moreover, the prevalence of OCD and obsessive-compulsive symptoms (OCS) and their impact on the quality of life of adolescents have not been extensively studied. The present dissertation comprises two studies, namely: 1) a population-based study designed to investigate the prevalence of OCS and OCD among adolescents, comparing demographic and clinical characteristics according to gender; and 2) a comparison between adolescents with and without OCD in relation to quality of life and the association between clinical characteristics and domain-specific quality of life impairment. Our results revealed a prevalence of 3.3% of OCD and 18.3% of OCS in the sample assessed, with girls presenting higher prevalence rates when compared with boys. Notwithstanding, despite the high rates observed, only a limited number of adolescents had been diagnosed with OCD before the study (9.3%), and an even smaller group was under treatment for the disorder (6.7%). In addition, when compared with adolescents without OCD, the group with the disorder showed poorer scores in all quality of life domains assessed. Also, the presence of depressive symptoms showed an association with poorer quality of life. These findings suggest that, in spite of the high prevalence of OCD, the disorder is still underdiagnosed and undertreated among adolescents. In addition, our findings confirm the significant impact of OCD on the quality of life of young patients, affecting all related domains.

Thesis (M. A. (Clinical Psychology)) University of Limpopo, 2017 / The study investigated the prevalence of Obsessive-Compulsive Disorder (OCD) symptoms and their relationship with pregnancy-related anxiety, prenatal depression and clinical anger among African pregnant women. The sample consisted of 206 pregnant women attending their antenatal check-ups at the Mankweng, Nobody and Rethabile clinics, and Mankweng hospital in the Capricorn District, Limpopo Province. When correlational analysis was conducted, the patient characteristics of age, having undergone a medical check-up, and having previously delivered a live baby generally did not correlate with any of the main scales measuring OCD, namely, perinatal depression, pregnancy-related anxiety and clinical anger (p > 0.05). Findings from the study indicated that almost 81% of the pregnant women could be classified as obsessive-compulsive disordered, when using the Foa et al. (2002) cut-off score of 21. Furthermore, findings from the regression analyses indicated that higher age, the number of gestation weeks, having previously experienced pregnancy-related complications, perinatal depression, pregnancy-related anxiety and clinical anger were variably positive predictors of OCI-R measured OCD symptoms. The predictors are specific to each of the symptoms. It can be concluded from the study that there is a relationship between OCD symptoms and all the independent variables used. / National Research Foundation

Die Zwangsstörung ist durch sehr verschiedenartige Symptome charakterisiert. Diese Symptomheterogenität stellt Herausforderungen für die psychologische Diagnostik dar. Die Yale-Brown Obsessive Compulsive Scale (Y-BOCS) gilt als der Goldstandard bei der Messung von Zwangssymptomen. Mittels einer großen Stichprobe von Zwangspatienten hatte diese Arbeit drei Ziele zur Weiterentwicklungen psychometrischer Methoden: Erstens wurden die Messmodelle von Zwangssymptomen evaluiert und verbessert. Dabei fand eine umfassende Überarbeitung statt, wobei Bayesianische Messmodelle genutzt wurden. Zweitens wurde getestet, ob die Messeigenschaften der Y-BOCS über die Zeit und für weitere klinische relevante Variablen konstant sind. In einer breit angelegten Messinvarianzanalyse wurden nur wenige Verletzungen der Messinvarianz gefunden. Falls solche vorliegen, werden Gruppenvergleiche verzerrt und eventuell falsche Schlussfolgerungen gezogen. Für diese Situationen wurde drittens eine Erweiterung partieller Messinvarianzmodelle entwickelt und angewendet. Partielle Messinvarianzmodelle ermöglichen valide Gruppenvergleiche auch dann, wenn Messinvarianz nur für einige wenige Items hält. Es wurde eine Methode zur Modellmittelung entwickelt, die die Unsicherheit berücksichtigt, die in der Auswahl von Items für partielle Messinvarianz liegt. Das entwickelte Bayesianische Verfahren macht Analyseentscheidungen komplett sichtbar und damit diskutierbar. Die vorgelegten Studien dienen der Weiterentwicklung psychometrischer Analysen in der klinischen Diagnostik im Allgemeinen und stärken die Validität der Messung durch die Y-BOCS im Besonderen. Klinische Studien können vertrauenswürdige Ergebnisse nur aufbauend auf soliden Messverfahren erzielen. Außerdem werden weitere neuere Entwicklungen in der psychometrischen Theorie im Hinblick auf ihren Nutzen in der klinischen Diagnostik und dem Verständnis der Zwangsstörung diskutiert. / Obsessive-compulsive disorder (OCD) is characterized by heterogeneous symptoms. Like for many clinical phenomena, this heterogeneity in symptoms poses challenges to psychological assessment. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) has developed into a gold standard within the past three decades. Using a large sample of patients suffering from OCD, we worked towards three goals in order to advance psychometric methods: First, evaluating and improving the measurement models associated with OCD symptoms by means of an exhaustive overhaul and the usage of Bayesian measurement modeling. Second, to test whether the Y-BOCS' measurement properties are stable across time and other features relevant to clinical research. In a broad analysis of measurement invariance (MI), we found only few instances where MI did not hold. Under such circumstances, group comparisons may be biased and conclusions could be misleading. For such situations, we thirdly derived and applied a procedure extending partial MI modeling. In partial MI models, group comparisons are still valid, even if MI holds only for a few items. We developed a model averaging approach that appropriately reflects the uncertainty stemming from choosing items for partial MI models. The developed Bayesian procedure makes decisions made during the analysis fully transparent and thus open to discussion. The presented studies form a research program that advances psychometrical analyses in clinical assessment and increases the validity of the assessment of OCD by means of the Y-BOCS. Clinical trials require such sound measurements in order to provide trustworthy conclusions. Furthermore, we discuss other recent advances in the field of psychometry and their usability for clinical research as a whole and the understanding of OCD specifically.

Text in English / This exploratory study creates a post-modern narrative context for psychotherapy and extends these ideas to an individual living with a psychiatric disorder, namely obsessive-compulsive disorder. The present study explores OCD through the ecosystemic perspective and aims to obtain a holistic understanding of an individual's experience of living with OCD and to describe the recursive connections between OCD and the individual's ecological context. This investigation includes the re-authoring therapy of Michael White and David Epston and the application of their ideas to the individual's life story. A qualitative method within the naturalistic paradigm is employed focussing on the unique experience of the individual, which allows for an understanding of the individual's personal meaning. The dominant narratives, that emerged from the individual's life story, were deconstructed. Significant shifts in attribution of meaning took place. / Psychology / M.A.(Clinical Psychology)