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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/19518 |
| Date | 03 1900 |
| Creators | Emsley, Robin |
| Contributors | Stein, Dan, Stellenbosch University. Faculty of Health Sciences. Dept. of Psychiatry. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 298 leaves : ill. |
| Rights | Stellenbosch University |
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