Biological and Clinical Determinants of Treatment Resistant Schizophrenia

Student thesis: Doctoral ThesisDoctor of Philosophy


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.
Date of Award2014
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRobin Murray (Supervisor) & Oliver Howes (Supervisor)

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