Alice Egerton

• PhD
• Professor (Associate) at King's College London

Molecular neuroimaging techniques, like PET and SPECT, offer invaluable insights into the brain’s in-vivo biology and its dysfunction in neuropsychiatric patients. However, the transition of molecular neuroimaging into diagnostics and precision medicine has been limited to a few clinical applications, hindered by issues like practical feasibility,...

Background Psychosis-relevant preclinical studies have demonstrated GABAergic drugs such as benzodiazepines can downregulate hippocampal hyperactivity and prevent the emergence of psychosis- like phenotypes. However, whether benzodiazepines can reduce and normalise increased hippocampal resting cerebral blood flow (rCBF) observed in individuals at...

Dysregulation of inflammatory mediators and complement cascade proteins has been implicated in psychosis. In the current study, we aimed to investigate the relationship between complement cascade proteins and inflammatory cytokines in blood from people at clinical high risk (CHR) for psychosis and at first episode of psychosis (FEP). Baseline blood...

Preclinical evidence suggests that modulating neural excitation through diazepam administration, a positive allosteric modulator of GABA A receptors, can prevent the emergence of behavioural and neurobiological alterations relevant to psychosis in adulthood. Here, we examined this neurochemical mechanism in individuals at clinical high-risk for psy...

PET and SPECT studies in treatment-resistant schizophrenia (TRS) have revealed significant alterations in regional cerebral blood flow (CBF) during clozapine treatment, which may vary according to the clinical response. Here, we used the more recent MRI approach of arterial spin labelling (ASL) to evaluate regional CBF in participants with TRS ( N...

Background Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential tre...

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle...

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medi...

Neuroimaging studies indicate that in treatment resistant schizophrenia (TRS), alterations in regional cerebral blood flow (CBF) during clozapine treatment may vary according to the clinical response. To date, these studies have involved radiotracers. Here, we used arterial spin labelling (ASL) to compare CBF in participants with TRS (N=36) before...

Background and Hypothesis Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown. Study...

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behaviour, and understanding the relationships between these layers may be fundamental to advancing our understanding of how the brain works in health and disease. Recent neuroimaging research has shown that alterations in brain fu...

Background Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which hae...

Background Elevated hippocampal perfusion has been observed in people at clinical high-risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that prophylactic treatment with diazepam during adolescence can prevent the development of psychosis-relevant phenotypes....

The second-generation antipsychotic clozapine is used as a medication for treatment-resistant schizophrenia. It has previously been associated with epigenetic changes in pre-clinical rodent models and cross-sectional studies of treatment-resistant schizophrenia. Cross-sectional studies are susceptible to confounding, however, and cannot disentangle...

Abstract Background and hypothesis: Use of clozapine in treatment-resistant schizophrenia is often limited due to risk of adverse effects. Cross-sectional associations between clozapine treatment and low immunoglobulin levels have been reported, however prospective studies are required to establish temporal relationships. We tested the hypothesis t...

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants...

Background Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences the risk of psychosis in humans is unknown. Methods This observational-cohort study used electronic health record data f...

The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psych...

Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia...

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside indivi...

Background and hypothesis: Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsych...

Introduction The impact of the clinical high-risk for psychosis (CHR-P) construct is dependent on accurately predicting outcomes. Individuals with brief limited intermittent psychotic symptoms (BLIPS) have higher risk of developing a first episode of psychosis (FEP) compared to individuals with attenuated psychotic symptoms (APS). Supplementing sub...

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (l...

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (l...

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked...

Objectives This prospective cohort study tested for associations between baseline cognitive performance in individuals early within their first episode and antipsychotic treatment of psychosis. We hypothesised that poorer cognitive functioning at the initial assessment would be associated with poorer antipsychotic response following the subsequent...

Glutamatergic dysfunction is implicated in the pathoaetiology of schizophrenia, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to cont...

Introduction Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC),...

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutama...

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked...

Background Clozapine is the only licensed pharmacotherapy for patients with treatment-resistant schizophrenia (TRS), but its use is limited due to adverse effects. Clozapine treatment has been recently associated with reductions in immunoglobulin (Ig) levels cross-sectionally, however prospective studies are required to establish longitudinal effec...

Background Clozapine is the only drug licensed for treatment-resistant schizophrenia (TRS) but the real-world clinical and cost-effectiveness of community initiation of clozapine is unclear. Aims The aim was to assess the feasibility and cost-effectiveness of community initiation of clozapine. Method This was a naturalistic study of community pat...

Importance: Previous in vitro and postmortem research suggests that inflammation may lead to structural brain changes via activation of microglia and/or astrocytic dysfunction in a range of neuropsychiatric disorders. Objective: To investigate the relationship between inflammation and changes in brain structures in vivo and to explore a transcri...

The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia befor...

Background 70%–84% of individuals with antipsychotic treatment resistance show non-response from the first episode. Emerging cross-sectional evidence comparing cognitive profiles in treatment resistant schizophrenia to treatment-responsive schizophrenia has indicated that verbal memory and language functions may be more impaired in treatment resist...

Glutamate signalling is increasingly implicated across a range of psychiatric, neurological and pain disorders. Reliable methodologies are needed to probe the glutamate system and understand glutamate dynamics in vivo. Functional magnetic resonance spectroscopy (¹H-fMRS) is a technique that allows measurement of glutamatergic metabolites over time...

Rationale Proton magnetic resonance spectroscopy (¹H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings...

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high r...

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective: To...

Background: Peripheral immune markers have previously been linked to a poor response to antipsychotic medication and more severe negative symptoms at the onset of psychosis. The present study investigated the association of blood cytokines and complement markers with the presence of antipsychotic non-response and symptom severity in patients with...

Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We s...

Recent findings implicate the complement C4 gene in gray matter loss in schizophrenia. In a large cohort of patients with first episode psychosis (FEP) we aimed to i) characterize the frequency of C4 gene copy number variations (CNVs) and HERV-K Ins/Del events as compared to that in healthy controls (HC), ii) evaluate whether C4 gene structural var...

It has been suggested that the antipsychotic clozapine may modulate brain glutamate, and that this effect could contribute to its efficacy in treatment-resistant schizophrenia (TRS). The aim of this study was to examine the effects of clozapine on brain glutamate in TRS longitudinally. This study examined individuals with TRS before and 12 weeks af...

Background Preclinical models propose that the onset of psychosis involves increased hippocampal activity which drives subcortical dopaminergic dysfunction. We used multi-modal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CH...

Purpose The conversion of synaptic glutamate to glutamine in astrocytes by glutamine synthetase (GS) is critical to maintaining healthy brain activity and may be disrupted in several brain disorders. As the GS catalysed conversion of glutamate to glutamine requires ammonia, we evaluated whether [¹³N]ammonia positron emission tomography (PET) could...

Background When psychosis develops in NMDAR antibody encephalitis it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first episode psychosis (FEP), but their role in psychosis onset and response to ant...

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus f...

Research into the neurobiological processes that may lead to the onset of schizophrenia places growing emphasis on the glutamatergic system and brain development. Preclinical studies have shown that neurodevelopmental, genetic, and environmental factors contribute to glutamatergic dysfunction and schizophrenia-related phenotypes. Clinical research...

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate...

Purpose The conversion of synaptic glutamate to glutamine in astrocytes by glutamine synthetase (GS) is critical to maintaining healthy brain activity and may be disrupted in several brain disorders. As the GS catalysed conversion of glutamate to glutamine requires ammonia, we evaluated whether [¹³N]ammonia positron emission tomography (PET) could...

Purpose: The conversion of synaptic glutamate to glutamine in astrocytes by glutamine synthetase (GS) is critical to maintaining healthy brain activity and may be disrupted in several brain disorders. As the GS catalysed conversion of glutamate to glutamine requires ammonia, we evaluated whether [¹³N]ammonia positron emission tomography (PET) could...

Background The mechanisms that underlie and may mediate the therapeutic response to clozapine in treatment resistant schizophrenia (TRS) are unclear. Basic science studies have indicated that clozapine may modulate brain glutamate, but this has not yet been investigated in man. The aim of this study was to determine whether clozapine alters brain g...

Background Striatal dopamine dysfunction is proposed to underlie symptoms in psychosis, yet it is not known how changes in a single neurotransmitter could underlie the heterogenous presentations that are seen clinically. One hypothesis is that the symptomatic consequences of aberrant dopamine signalling may depend on where within the striatum dysfu...

Background Approximately one third of patients with schizophrenia display suboptimal response to two trials of non-clozapine antipsychotic medication and may be termed treatment resistant. Clozapine is the only licensed pharmacotherapy for treatment resistant schizophrenia, but response to clozapine is variable and can only be determined through a...

Background Proton Magnetic Resonance Spectroscopy (1H-MRS) studies indicate that altered brain glutamate signalling contributes to the pathophysiology of schizophrenia and treatment response. However it is unclear whether clinical and demographic factors affect glutamate levels in the brain. Here we aim to determine the effects of age, antipsychoti...

Background Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signalling vary depending on where within the striatum the dysfunction occurs. Po...

Rationale There is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce. Objectives The aim of this study was to identify the changes in resting-state functional connectivity (rs-FC) that occur following administration of a single do...

Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment, and also indicate that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatment is unclear. He...

Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered i...

Cannabis use has been associated with adverse mental health outcomes, the neurochemical underpinnings of which are poorly understood. Although preclinical evidence suggests glutamatergic dysfunction following cannabis exposure in several brain regions including the hippocampus, evidence from human studies have been inconsistent. We investigated the...

Rationale Anterior cingulate cortex (ACC) glutamatergic abnormalities are reported in treatment-resistant schizophrenia (TRS) and implicated in functional dysconnectivity and psychopathology. Preclinical evidence indicates riluzole reduces synaptic glutamate. However, it is unknown whether riluzole can modulate glutamate metabolite levels and assoc...

Background Neuroimaging studies in schizophrenia have linked elevated glutamate metabolite levels to non-remission following antipsychotic treatment and have also indicated that antipsychotics can reduce glutamate metabolite levels. However, the relationship between symptomatic reduction and change in glutamate during initial antipsychotic treatmen...

Resting-state fMRI striatal connectivity in high and low schizotypy.

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (G...

Disrupted striatal functional connectivity is proposed to play a critical role in the development of psychotic symptoms. Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies typically reported disrupted striatal connectivity in patients with psychosis and in individuals at clinical and genetic high risk of the disorder rel...

Rationale N-Acetylcysteine (NAC) is currently under investigation as an adjunctive treatment for schizophrenia. The therapeutic potential of NAC may involve modulation of brain glutamate function, but its effects on brain glutamate levels in schizophrenia have not been evaluated. Objectives The aim of this study was to examine whether a single dos...

Background: The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamin...

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Background: Clozapine is the recommended antipsychotic for treatment-resistant schizophrenia (TRS) but there is significant variability between patients in the degree to which clozapine will improve symptoms. The biological basis of this variability is unknown. Although clozapine has efficacy in TRS, it can elicit adverse effects and initiation is...

Background: Elevated striatal dopamine synthesis capacity has been implicated in the etiology and antipsychotic response in psychotic illness. The effects of antipsychotic medication on dopamine synthesis capacity are poorly understood, and no prospective studies have examined this question in a solely first-episode psychosis sample. Furthermore,...

Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have rep...

Background The response to antipsychotic treatment in patients with psychosis is difficult to predict on the basis of the patient’s clinical features. As a result, patients are generally treated in a similar way, even though their response can vary dramatically. Recent neuroimaging studies suggest that the pattern of brain abnormalities in patients...

Background Approximately one-third of schizophrenia patients will not respond adequately to conventional antipsychotic treatment; termed treatment-resistant schizophrenia (TRS). The only antipsychotic recommended for this group is clozapine, which may have unique efficacy in improving residual symptoms. The biological mechanisms underlying its effi...

Background Schizophrenia may be associated with elevations in glutamate levels in the anterior cingulate cortex (ACC), and this may be particularly apparent in patients who have not responded well to conventional antipsychotic treatment (Egerton et al., 2012; Mouchliantis et al., 2016). This suggests that compounds that can decrease ACC glutamate l...

Background The continuum approach to psychosis proposes a dimensional continuity between the neurobiology of subclinical psychotic-like experiences in healthy individuals (or schizotypy) and psychotic symptoms in clinically relevant psychosis (Linscott and van Os, 2013, Nelson et al., 2013). Preclinical models propose that cortical glutamate dysfun...

Use of Cannabis, the most widely used illicit drug worldwide, is associated with acute anxiety, and anxiety disorders following regular use. The precise neural and receptor basis of these effects have not been tested in man. Employing a combination of functional MRI (fMRI) and positron emission tomography (PET), we investigated whether the effects...

Background: Cortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high s...