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Title: Biological and clinical determinants of treatment resistant schizophrenia
Author: Demjaha, Arsime
ISNI:       0000 0004 5349 629X
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2014
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Up to one third of patients with schizophrenia show only limited response to dopamine blocking antipsychotic medication. This could be due to distinct neurobiological abnormalities in this subgroup of patients. While there is robust evidence to suggest that the neurobiology of schizophrenia involves increased presynaptic striatal dopaminergic elevation, little is known as to whether this abnormality is present in treatment resistance, and consequently the relationship between this dopamine abnormality and the lack of response to treatment remains unknown. Furthermore, it remains unclear whether treatment resistance manifests at the outset of illness, and perhaps has a neurodevelopmental origin, or whether it evolves over time, possibly as a result of a neurodegenerative process. The first study in this thesis investigated striatal presynaptic dopamine synthesis in twelve treatment resistant schizophrenic patients, twelve patients with schizophrenia who had responded to antipsychotics, and twelve healthy volunteers, using [18F]-DOPA Positron Emission Tomography (PET). Thus, it was possible to test the hypothesis that the response to treatment is determined by differences in presynaptic dopamine function. The results demonstrated that there were no significant differences in striatal dopamine synthesis capacity between treatment resistant patients and healthy volunteers, whilst dopamine synthesis capacity was significantly increased in responders relative to treatment resistant patients. The difference was most marked in the associative and the limbic striatal subdivisions. A second, large follow-up study of first episode psychosis (FEP) patients, examined the course of treatment resistance over the 10 year follow up. It was found that over 80% of treatment resistant patients were persistently resistant from the initiation of antipsychotic treatment. My PET study, due to its cross sectional design, could not determine whether the normal dopamine levels predate the antipsychotic exposure in treatment resistant patients. However, by demonstrating that a great majority of treatment resistant patients are resistant to dopamine blocking antipsychotics at first ever initiation of treatment, my second study raises the possibility that these patients may have had normal dopamine levels even at the outset of their psychotic illness. In the same FEP cohort it was possible to investigate neurodevelopmental predictors of treatment resistance. The finding that the negative symptom dimension and younger age of onset were significant predictors of treatment resistance is compatible with the view that TRS may be of neurodevelopmental origin. Overall, my observations in this thesis indicate that TRS may be a distinct and enduring subtype of schizophrenic illness of a possible neurodevelopmental origin whose pathophysiology is not marked by alterations in dopamine synthesis capacity. Findings emerging from this thesis provide a platform for future studies, which may lead to the discovery of much needed new treatments for this disabling and intractable condition.
Supervisor: Demjaha, Arsime Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available