Studies in the psychopathology, neurobiology and psychopharmacology of schizophrenia

Emsley, Robin A. (2008-03)

Dissertation (DSc)-- Stellenbosch University, 2008.


ENGLISH ABSTRACT: The overall aim of these studies was to investigate selected aspects of psychopathology, neurobiological abnormalities and treatment in schizophrenia. The following topics were researched: 1. Psychopathology: We explored the symptom structure of schizophrenia by means of principal components and factor analysis in two separate samples. a. The first study investigated the nature of symptoms in patients with a first-episode of schizophrenia, in a large cohort of patients who were participating in a multinational clinical trial. We compared our findings with similar analyses previously conducted in multi-episode schizophrenia patients. b. We then assessed the influence of culture on the symptom structure of schizophrenia by conducting a principal components and factor analysis of the symptom ratings in a large sample of South African Xhosa patients with schizophrenia, and comparing the results with those in other parts of the world. c. We investigated the occurrence of co-morbid depressive and anxiety symptoms, and their demographic and clinical correlates. The sample for this study comprised acutely psychotic patients who were participants in clinical drug trials conducted at our centre. d. To explore the relationships between obsessive-compulsive disorder and schizophrenia, we conducted a review of the relevant literature. 2. Neurobiological abnormalities: a. We performed a series of studies to investigate disorders of water homeostasis and vasopressin secretion in schizophrenia. To test the hypothesis that acutely psychotic patients have disordered regulation of water homeostasis, we applied a dynamic suppression test - a water loading test, with assessment of excretory capacity (including arginine vasopressin assay) in acutely psychotic patients. To evaluate whether a subset of patients with schizophrenia and co-morbid disordered water homeostasis sustained cerebral damage as a consequence of water intoxication we did the following experiment: We identified a cohort of subjects with schizophrenia and disordered water homeostasis and compared them with patients with schizophrenia without disordered water homeostasis in terms of cerebral ventricular size and cognitive function. To assess the prevalence of disordered water homeostasis in a long-term inpatient sample of psychiatric patients we conducted serum sodium screening tests. Those subjects with dilutional hyponatraemia were then further investigated for dysregulation of water homeostatic mechanisms. b. We studied neurological soft signs in a sample of subjects with first-episode schizophrenia followed up over a two year period. We investigated their occurrence, relationships to psychiatric symptoms and medication effects, their temporal stability and their outcome correlates. We also investigated their potential to predict outcome in schizophrenia 3. Treatment aspects A great deal of our work has focussed on the pharmacological treatment of schizophrenia. The following aspects of treatment are included in this thesis: a. Treatment effects on psychiatric symptoms: i. To assess the effects of ethnicity on treatment outcome in schizophrenia we compared the acute response to antipsychotic treatment in 3 ethnic groups, namely blacks, coloureds and whites. We included patients in this analysis who had participated in clinical trials in our department as well as the Department of Psychiatry in the University of the Free Sate. Patients had been treated under blinded conditions over a 6-week period. ii. After discussions with the late Dr David Horrobin, who had pioneered possible applications of the omega-3 fatty acids in the treatment of various psychiatric disorders, we became interested in further investigating the potential of this group of compounds as an affordable adjunct to treating schizophrenia. We assessed the antipsychotic potential of the omega-3 fatty acid, ethyl-eicosapentaenoic-acid (e-EPA) supplementation versus placebo supplementation in a small sample of subjects with schizophrenia who had been only partially responsive to antipsychotic treatment previously. We also conducted a review of the literature to evaluate the evidence for efficacy for the omega-3 fatty acids in schizophrenia according to published studies. b. Treatment effects on neurological abnormalities: i. In a single-blinded controlled study we compared a new generation antipsychotic to a conventional antipsychotic in the treatment of tardive dyskinesia (TD). This was a long-term (1 yr) study in patients with chronic schizophrenia and established tardive dyskinesia. ii. We also assessed the effect of omega-3 fatty acid (e-EPA) supplementation in treating TD. This was conducted in a larger sample (n=84) of patients with chronic schizophrenia and established TD. The blinded, placebo-controlled phase was 12 weeks. This was followed by an open-label extension for 40 weeks. c. Conventional versus new generation antipsychotic agents. Several evidence-based literature reviews of the efficacy and tolerability of the new generation of antipsychotics compared to the conventional agents were conducted. Some multinational, randomised, controlled clinical trials in which the author was principal investigator, are included in this thesis. Also, studies addressing patients with partial treatment refractoriness are included, as well as studies of the effects of antipsychotics on depressive symptoms, body mass and glycaemic control. Finally, we have included a pharmacoeconomic study comparing a conventional antipsychotic (haloperidol) with a new generation antipsychotic (quetiapine) in partially refractory patients in a South African setting. Findings and conclusions: 1. Psychopathology: Our studies demonstrated that the factor structure for the symptoms of schizophrenia is replicable across samples, and is not greatly influenced by ethnic and cultural factors. However, changes in the factor structures do occur over time. There are symptom domains that are present in first-episode schizophrenia but disappear as a distinct entity as the illness becomes chronic. Particularly, a motor component is evident in untreated patients, but disappears after initiation of treatment. We found that depression and anxiety are common co-morbid symptoms in schizophrenia, and have important clinical and outcome correlates. Depressive symptoms in the acute psychotic phase of schizophrenia are associated with a favourable prognosis and diminish as the symptoms of psychosis improve in response to antipsychotic treatment. However, persistent depressive symptoms are associated with a poorer prognosis, and require additional therapeutic intervention. 2. Neurobiological abnormalities: We investigated the occurrence of disordered water regulation in a population of psychiatric inpatients, and conducted further investigations on those identified, in order to establish mechanisms involved. Polydipsia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) were found to occur in a subset of patients with schizophrenia, and are associated with acute psychosis, as well as with some psychotropic medications. These patients are characterised by more severe cognitive impairment and evidence of cerebral atrophy. The condition can become life-threatening in the presence of other factors impeding water excretion, particularly thiazide diuretics. Neurological soft signs were investigated in a sample of patients with a first-episode of schizophrenia. These soft signs appear to be trait-like (present early in the illness, and stable over time), except for a motor sequencing factor. Patients performing poorly on this latter group of tests have a longer duration of untreated psychosis, and are at significant risk for developing TD. 3. Treatment aspects: Our studies suggest that there are important ethnic differences in antipsychotic treatment response, but that these differences could be explained by a number of environmental and biological factors. As was found with many studies worldwide, we found that the new generation antipsychotics have important efficacy and safety advantages over their predecessors. Risperidone was as effective as haloperidol in first-episode psychosis, but with a more favourable side-effect profile in terms of reduced extrapyramidal symptoms. Quetiapine treatment in partially refractory patients resulted in more responders compared to haloperidol, and fewer extrapyramidal symptoms. However, evidence of a different side-effect profile is emerging. Of particular concern is the finding that some of the new antispychotics cause weight gain, glucose intolerance and dyslipidaemias. We found that one novel antipsychotic, quetiapine, was not associated with significantly more weight gain or disordered glucose metabolism that a conventional agent, haloperidol. The omega-3 fatty acids, particularly EPA may have a role in the treatment of various psychiatric disorders. Our studies provided mixed results – the first found a significant beneficial effect on psychotic symptoms and dyskinesia scores for EPA supplementation, while the second failed to demonstrate a beneficial effect on TD or psychotic symptoms. We explored the early treatment response in first-episode psychosis and found, unlike that reported in multi-episode patients, some patients took a long time to respond. We also found that early treatment response was a significant predictor of later remission, as was duration of untreated psychosis, educational level and baseline excitement factor scores. Finally, our pharmacoeconomic study conducted for South African circumstances in patients with a partial response to conventional antipsychotic treatment showed cost-neutrality or cost-benefits for quetiapine compared with haloperidol treatment for direct costs.

AFRIKAANSE OPSOMMING: Die oorkoepelende doel van hierdie studies was om geselekteerde aspekte van psigopatologie, neurobiologiese abnormaliteite en behandeling in skisofrenie te ondersoek. Die volgende onderwerpe is nagevors: 4. Psigopatologie: Ons het die simptoomstruktuur van skisofrenie ondersoek deur middel van hoofkomponent- en faktoranalise in twee aparte steekproewe. a. Die eerste studie het die aard van simptome in pasiënte, met ʼn eerste-episode van skisofrenie, ondersoek in ʼn groot kohort van pasiënte wat deelgeneem het aan ʼn multi-nasionale kliniese proefneming. Ons het ons bevindinge vergelyk met soortgelyke analises wat voorheen gedoen is in multi-eposode skisofrenie pasiënte. b. Hierna het ons die invloed van kultuur op die simptoom struktuur van skisofrenie geassesseer deur ʼn hoofkomponent- en faktoranalise van die simptoomtellings uit te voer in ʼn groot steekproef van Suid-Afrikaanse Xhosa pasiënte met skisofrenie en die resultate te vergelyk met bevindinge in ander dele van die wêreld. c. Ons het die voorkoms van ko-morbiede depressiewe en angssimptome ondersoek, asook hul demografiese en kliniese korrelate. Die steekproef vir hierdie studie het bestaan uit akute psigotiese pasiënte wat deelnemers was in ʼn kliniese geneesmiddel proef wat uitgevoer is by ons sentrum. d. Om die verband tussen obsessief-kompulsiewe steurnis en skisofrenie te verken, het ons ʼn oorsig van die relevante literatuur gedoen. 5. Neurobiologiese abnormaliteite: a. Ons het ʼn reeks studies uitgevoer om steurnisse in water homeostase en vasopressien sekresie in skisofrenie te ondersoek. Om die hipotese dat akute psigotiese pasiënte versteurde regulering van water homeostase het te ondersoek, het ons ʼn dinamiese onderdrukkingstoets toegepas – ʼn water ladingstoets, met assessering van ekskresiekapasiteit (insluitend arginien vasopressien essai) in akute psigotiese pasiënte. Om te evalueer of ʼn onderafdeling van skisofrenie pasiënte met ko-morbiede versteurde water homeostase serebrale skade opgedoen het as gevolg van water intoksikasie, het ons die volgende eksperiment uitgevoer: Ons het ʼn kohort deelnemers met skisofrenie en versteurde water homeostase geïdentifiseer en hulle vergelyk met skisofrenie pasiënte sonder versteurde water homeostase in terme van serebrale ventrikulêre grootte en kognitiewe funksionering. Om die voorkoms van versteurde water homeostase in ʼn langtermyn binne-pasiënt steekproef van psigiatriese pasiënte te bepaal, het ons serum natrium siftingstoetse uitgevoer. Deelnemers met hiponatremie is hierna verder ondersoek vir disregulering van water homeostatiese meganismes. b. Ons het neurologiese sagte tekens in ʼn steekproef van deelnemers met eersteepisode skisofrenie bestudeer en opgevolg oor ʼn twee jaar tydperk. Ons het hulle voorkoms, verwantskappe met psigiatriese simptome en medikasie effekte, hulle temporale stabiliteit en hul uitkoms korrelate ondersoek. Ons het ook hulle potensiaal om die uitkoms in skisofrenie te voorspel, ondersoek. 6. Behandelings aspekte ʼn Groot meerderheid van ons werk het gefokus op die farmakologiese behandeling van skisofrenie. Die volgende aspekte van behandeling is ingesluit in hierdie tesis: a. Behandelingseffekte op psigiatriese simptome: i. Om die effek van etnisiteit op behandelingsuitkoms in skisofrenie te assesseer, het ons die akute respons op anti-psigotiese behandeling in 3 etniese groepe vergelyk, naamlik swart, gekleurd, en wit. Ons het pasiënte wat deelgeneem het aan kliniese proefnemings in ons departement sowel as die Departement Psigiatrie van die Universiteit van die Vrystaan ingesluit in hierdie analise. Pasiënte is behadel onder geblinde toestande oor ʼn tydperk van 6 weke. ii. Na besprekings met wyle Dr David Horrobin, wie die moontlike toepassings van omega-3 vetsure in die behandeling van verskeie psigiatreise steurnisse gepionier het, het ons begin belangstel in verdere ondersoek na die potensiaal van hierdie groep samestellings as ʼn bekostigbare toevoeging in die behandeling van skisofrenie. Ons het die anti-psigotiese potensiaal van die omega-3 vetsuur, etieleikosapentanoësuur (e-EPA) supplementasie versus plasebo supplementasie ondersoek in ʼn klein steekproef van deelnemers met skisofrenie wat slegs gedeeltelik responsief was op anti-psigotiese behandeling in die verlede. Ons het ook ʼn literatuuroorsig gedoen om die bewyse vir die effektiwiteit vir die omega-3 vetsure in skisofrenie te evalueer volgens gepubliseerde studies. b. Behandelingseffekte op neurologiese abnormaliteite: i. In ʼn enkelblinde kontrole studie het ons ʼn nuwe generasie anti-psigotiese medikasie vergelyk met ʼn konvensionele anti-psigotiese medikasie in die behandeling van tardiewe diskinesie (TD). Hierdie was ʼn langtermyn (1- jaar) studie in pasiënte met chroniese skisofrenie en vasgestelde TD. ii. Ons het ook die effek van omega-3 vetsuur (e-EPA) suplementasie geassesseer in die behandeling van TD. Dit was gedoen in ʼn groter steekproef (n=84) van pasiënte met chroniese skisofrenie en vasgestelde TD. Die blinde, placebo kontrole fase was 12 weke. Dit is gevolg deur ʼn nie-geblinde ekstensie vir 40 weke. c. Konvensionele versus nuwe generasie anti-psigotiese agente. Verskeie bewys-gebaseerde literatuuroorsigte oor die effektiwiteit en toleransie van die nuwe generasie anti-psigotiese agente in vergelyking met die konvensionele agente, is gedoen. Sommige multi-nasionale, ewekansige, kontole kliniese proefnemings waarin die outeur die hoofnavorser was, is ingesluit in hierdie tesis. Verder, studies wat die pasiënte met gedeeltelike behandelingsweerstandigheid aanspreek, is ingesluit, sowel as studies oor die effekte van anti-psigotiese agente op depressiewe simptome, liggaamsmassa en glisemiese kontrole. Laastens, het ons a farmakoekonomiese studie ingesluit wat die konvensionele anti-psigotiese behandeling (haloperidol) met ʼn nuwe generasie anti-psigotiese behandeling (quetiapien) in gedeeltelik weerstandige pasiënte in ʼn Suid-Afrikaanse ligging vergelyk. Bevindinge en gevolgtrekkings: 4. Psigopatologie: Ons studies het gedemonstreer dat die faktor struktuur vir die simptome van skisofrenie herhaalbaar is oor steekproewe, en dat dit nie grootliks beïnvloed word deur etnisiteit en kulturele faktore nie. Veranderinge vind egter in die faktor strukture wel plaas met verloop van tyd. Daar is simptoom domeine wat teenwoordig is in eerste-episode skisofrenie, maar verdwyn as ʼn afsonderlike entiteit soos wat die toestand chronies word. Spesifiek, ʼn motoriese komponent is duidelik in onbehandelde pasiënte, maar verdwyn na die aanvang van behandeling. Ons het gevind dat depressie en angs algemene ko-morbiede simptome in skisofrenie is en het belangrike kliniese en uitkoms korrelate. Depressiewe simptome in die akute psigotiese fase van skisofrenie word geassosieer met ʼn gunstige prognose en verminder soos wat die simptome van psigose verbeter in repons op anti-psigotiese behandeling. Egter, volgehoue depressiewe simptome word geassosieer met ʼn swakker prognose en benodig addisionele terepeutiese intervensie. 5. Neurobiologiese abnormaliteite: Ons het die voorkoms van versteurde water regulering ondersoek in ʼn populasie van psigiatriese binne-pasiënte en verdere ondersoek ingestel op dié wie geïdentifiseer is, om die betrokke meganismes vas te stel. Polidipsie en en die sindroom van onvoldoende antidiuretiese hormoon sekresie (SIADH) is gevind om voor te kom in ʼn onderafdeling van pasiënte met skisofrenie, en word geassosieer met akute psigose sowel as met somige psigotropiese medikasie. Hierdie pasiënte word gekenmerk deur meer ernstige kognitiewe beperking en bewyse van serebrale atrofie. Die toestand kan lewensbedreigend raak in die teenwoordigheid van ander faktore wat water ekskresie hinder, veral tiasied diuretikums. Neurologiese sagte tekens is ondersoek in ʼn steekproef van pasiënte met eerste-episode skisofrenie. Hierdie sagte tekens blyk om kenmerkend (teenwoordig vroeg in die siekte, en stabiel oor tyd) te wees, behalwe vir ʼn motoriese volgorde faktor. Pasiënte wat swak vaar op die laasgenoemde groep toetse, het ʼn langer durasie van onbehandelde psigose, en het ʼn beduidende risko om TD te ontwikkel. 6. Behandeling aspekte: Ons studies stel voor dat daar ʼn belangrigke etniese verskil is in anti-psigotiese behandelingsrespons, maar dat hierdie verskille verduidelik kan word deur ʼn aantal omgewings- en biologiese faktore. Soos wat gevind was vir verskeie studies wêreldwyd, het ons gevind dat die nuwe generasie anti-psigotiese agente belangrike effektiwiteit- en veiligheidsvoordele het bo hulle voorgangers. Risperidoon was net so effektief as haloperidol in eerste-episode psigose, maar met ʼn meer gunstige newe-effkte profiel in terme van verminderde ekstrapirimidale simptome. Quetiapien behandeling in veral refraktêre pasiënte het gelei tot meer respondeerders vergeleke met haloperidol, en minder ekstra pirimidale simptome. Alhoewel, bewyse van ʼn verskillende newe-effekte profiel is besig om na vore te kom. Van spesifieke belang is die bevinding dat sommige van die nuwe anti-psigotiese agente gewigstoename, glukose intoleransie en dyslipidemie veroorsaak. Ons het gevind dat een nuwe anti-psigotiese agent, quetiapien, nie geassosieer was met enige beduidende meer gewigstoename of versteurde glukose metabolisme as ʼn konvensionele agent, haloperidol, nie. Die omega-3 vetsure, spesifiek EPA mag moontlik ʼn rol in die behandeling van verskeie psigiatriese versteurings hê. Ons studies het gemengde resultate voorsien – die eerste het ʼn beduidende voordelige effek op psigotiese simptome en diskinesie tellings vir EPA supplementasie gevind, terwyl die tweede nie ʼn voordelige effek op TD of psigotiese simptome gevind het nie. Ons het die vroeë behandelingsrespons ondersoek in eersteepisode pasiënte en het gevind, in teenstelling met dit wat gerapporteer word in multi-episode pasiënte, dat sommige pasiënte ʼn lang tyd geneem het om te reaggeer. Ons het ook gevind dat vroeë behandelingsrespons ʼn beduidende voorspeller was van latere remissie, so ook die durasie van onbehandelde psigose, opvoedingspeil, en basisvlak opwindings-faktor tellings. Laastens het ons farma-ekonomiese studie, wat uitgevoer is vir Suid-Afrikaanse omstandighede in pasiënte met ʼn gedeeltelike repons op konvensionele anti-psigotiese behandeling, koste-neutraliteit of koste-voordele aangetoon vir quetiapien vergeleke met haloperidol behandeling vir direkte onkostes.

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