Abstract
Early response to antipsychotic medication in schizophrenia has been found to be highly predictive of future response to pharmacological intervention. Recent research has reported that non-response as early as 2 weeks into antipsychotic treatment is associated with future non-response. Up to a third of individuals with a schizophrenia diagnosis will experience antipsychotic treatment resistance following multiple trials of antipsychotic medication with no or minimal remission of symptoms and are termed treatment resistant (TRS). Those with a resistant illness are recommended to have early intervention with clozapine, with earlier initiation associated with better clinical and functional outcomes. In comparison to those responsive to antipsychotic medication, TRS patients show greater glutamatergic abnormalities, a lack of dopaminergic abnormalities, an earlier onset of schizophrenia, are more likely to be male and have poor premorbid functioning. However, there is a need to understand other potential predictors of antipsychotic resistance and non-response, particularly early in the illness onset.Neuropsychological measures provide a cheap and non-invasive tool to examine cognitive performance and functioning in schizophrenic and other clinical populations. Cognitive deficits have long been documented in schizophrenia; in comparison to healthy controls, prior to illness onset, in unaffected relatives, and research has found deficits in adolescence to also be predictive of a future psychosis diagnosis. However, little is known about the relationship between cognitive performance and antipsychotic non-response and resistance; are those with a resistant illness more cognitively impaired than those who respond to antipsychotic medication? This thesis tackles this question by investigating the relationship between cognitive performance and antipsychotic response across the disease timeline; from secondary research, first episode samples, and known cases of antipsychotic response and non-response.
In Chapter 8 I meta-analysed the results from 17 published, mostly cross-sectional, studies comparing known samples of treatment resistant schizophrenia (TRS) and responsive schizophrenia on multiple measures of cognitive performance. Five metaanalyses were performed in relation to 1) executive function, 2) general cognitive function, 3) attention, working memory and processing speed, 4) verbal memory and learning, and 5) visual-spatial memory and learning. Small to moderate effect sizes emerged for all domains, with the largest effect size observed in verbal memory and learning. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size. These results are discussed in relation to the neurodevelopmental origins of treatment resistance and verbal functions in schizophrenia.
In Chapter 9 I then investigate the relationship between cognition and antipsychotic response in an international cohort of first episode psychosis patients, with follow-up data to prospectively categorise patients as responsive or resistant to antipsychotic treatment. Baseline cognitive data, originating from multiple cognitive tasks and seven international cohorts, was categorised in the similar manner to domains in Chapter 8. On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline assessment. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at first episode. These findings remained significant after adjusting for age, gender, cohort, duration of untreated psychosis, length of follow-up, and positive and negative symptoms. The findings and limitations are discussed, as well as the addition of cognitive performance to clinical markers of psychosis and future antipsychotic response.
Chapter 10 also utilises a cohort early in their antipsychotic treatment and illness onset. Here the sample was followed up at 3 study visits over a period of 6 weeks, providing cognitive (using the Brief Assessment of Cognition in Schizophrenia) and symptom severity (Positive and Negative Syndrome Scale) data at each visit. Trajectory analyses were used to classify the participants by treatment response from symptom severity data; 84.8% of the sample were classified as treatment responsive, and the remaining 15.2% as treatment non-responsive. Unadjusted and adjusted logistic regressions observed no significant relationship between baseline cognitive performance and antipsychotic response at 6 weeks. However larger samples may have been required to observe a meaningful difference between trajectory groups.
In Chapter 11, I discuss the results from a cross-sectional study with antipsychotic treatment responders and antipsychotic non-responders. Cognitive data were again collected using the Brief Assessment of Cognition in Schizophrenia, such as in Chapter 10. Univariable regression models observed no significant differences between antipsychotic responder and non-responder groups on any measure of the BACS. This pattern of findings was consistent in multivariable models. The lack of group difference in cognition in this sample is likely due to a lack of clinical distinction between groups or an absence of effect between early response and cognitive performance.
Finally, in Chapter 12 I discuss the findings from this thesis in the context of the current literature, clinical settings, and the future potential of including cognitive markers in clinical and demographic prediction models of antipsychotic response. In addition to this, I also provide recommendations for future research in the field as well as discuss the strengths and limitations of my findings.
| Date of Award | 1 Jul 2022 |
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| Original language | English |
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| Supervisor | James Maccabe (Supervisor) & Jenny Kravariti (Supervisor) |