Relationships between clinical, neurochemical and genetic features of antipsychotic response in schizophrenia

Student thesis: Doctoral ThesisDoctor of Philosophy


The burden of poor antipsychotic response in schizophrenia has a profound impact on patients, their caregivers and wider society. Patients who demonstrate a poor antipsychotic response may have some distinct clinical and biological features compared to those who respond well to antipsychotic treatment. Treatment-resistant schizophrenia is associated with more severe cognitive impairment and may have a distinct genetic loading to other more treatment responsive forms of illness. Most consistently, poor clinical and functional outcomes under antipsychotic treatment have been associated with elevations in glutamate metabolite concentrations in the anterior cingulate cortex. The overall aim of this work was to investigate the relationships between these features of poor antipsychotic response in schizophrenia, to better understand the aetiology of disease and ultimately aid the development of stratified treatment approaches.

The introductory chapter of this thesis provides an overview of schizophrenia, treatment resistance and features of poor antipsychotic response. As an extension of this literature synthesis, Chapter 2 is a systematic review and meta-analysis of clinical and demographic variables associated with response to clozapine treatment in treatment-resistant schizophrenia.

The three subsequent data chapters in this thesis examine relationships between glutamate in the anterior cingulate cortex and 1) neurocognitive function; 2) common genetic variation. I present data from STRATA-1, a multicentre cross-sectional study of patients with schizophrenia spectrum disorders displaying a good or poor response to antipsychotic treatment.

Brain glutamate may contribute to both clinical outcomes and cognition in schizophrenia, but these relationships are not well understood. In Chapter 4, I find that higher levels of glutamate in the anterior cingulate cortex are associated with better cognitive function. I also demonstrate that this relationship does not differ according to the degree of antipsychotic response in participants. This result suggests that the nature of the relationship between anterior cingulate cortex glutamate and cognition is similar between good and poor antipsychotic responders, at least within the range of glutamate and cognitive function measured in our sample.

Next, I investigate the common genetic architecture of anterior cingulate cortex glutamate concentrations in schizophrenia. In Chapter 5 I generate a treatment resistance polygenic score, which summarises the common genetic loading for treatment resistance. I find no association between the treatment resistance polygenic score and brain glutamate within the study sample. There was, however, some indication that the relationship between the treatment resistance polygenic score and anterior cingulate cortex glutamate was different between good and poor antipsychotic response groups.

Finally, in Chapter 6 I generate pathway polygenic scores. These were made from common genetic variants associated with an increased risk of treatment-resistant schizophrenia that fall within genes implicated in NMDA receptor function. I find evidence of a negative association between the treatment resistance NMDA receptor complex pathway polygenic score and brain glutamate.

In summary, I show that genetic liability for treatment-resistant schizophrenia within NMDA receptor encoding genes is associated with glutamate concentrations in the anterior cingulate cortex. In turn, these variations in glutamate are associated with verbal cognitive function in this disorder. These results are discussed within the wider context of novel drug development and personalised medicine for the treatment of schizophrenia spectrum disorders.

Date of Award1 Jun 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorAlice Egerton (Supervisor) & James Maccabe (Supervisor)

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