Alice Egerton

Bio: Alice Egerton is an academic researcher from King's College London. The author has contributed to research in topics: Psychosis & Schizophrenia. The author has an hindex of 41, co-authored 101 publications receiving 5073 citations. Previous affiliations of Alice Egerton include University of Strathclyde & Imperial College London.

Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.

Abstract: Objective:While there is robust evidence of elevated dopamine synthesis capacity once a psychotic disorder has developed, little is known about whether it is altered prior to the first episode of frank illness. The authors addressed this issue by measuring dopamine synthesis capacity in individuals at ultra-high risk of psychosis and then following them to determine their clinical outcome. Method:This prospective study included 30 patients who met standard criteria for being at ultra-high risk of psychosis and 29 healthy volunteers. Participants were scanned using [18F]6-fluoro-l-dopa positron emission tomography. The ultra-high-risk patients were scanned at presentation and followed up for at least 3 years to determine their clinical outcome. Six patients had comorbid schizotypal personality disorder and were excluded from the analysis (data are provided for comparison). Of the remaining patients, nine developed a psychotic disorder (psychotic transition group) and 15 did not (nontransition group). Resul...

Nature of Glutamate Alterations in Schizophrenia: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Abstract: Importance Alterations in glutamatergic neurotransmission may be fundamental to the pathophysiology of schizophrenia, and the glutamatergic system is a target for novel therapeutic interventions in the disorder. Objective To investigate the nature of brain glutamate alterations in schizophrenia by conducting a meta-analysis of glutamate proton magnetic resonance (MRS) spectroscopy studies. Data Sources The MEDLINE database was searched for studies published from January 1, 1980, to April 1, 2015. Search terms included magnetic resonance spectroscopy , schizophrenia , psychosis , clinical or genetic high risk, and schizoaffective . Inclusion criteria were single voxel 1H-MRS studies reporting glutamate, glutamine or Glx values for a patient or risk group in comparison to a healthy volunteer group. Study Selection Fifty-nine studies were identified, which included 1686 patients and 1451 healthy individuals serving as controls. Data Extraction and Synthesis A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were determined for glutamate, glutamine, and Glx in brain regions that had been examined in at least 3 different studies. A secondary analysis grouped studies into those examining patients at different stages of illness (high risk, first-episode psychosis, or chronic schizophrenia). Effects of age, antipsychotic dose, and symptom severity were determined using meta-regression. Results In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus ( g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia ( g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe ( g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in individuals at high risk for schizophrenia ( g = 0.26; 95% CI, 0.05-0.46) but not in those with first-episode psychosis or chronic schizophrenia, whereas elevated Glx in the medial temporal lobe was seen with chronic schizophrenia ( g = 0.40; 95% CI, 0.08-0.71) but not in the high-risk or first-episode groups. Meta-regression found no association with age, symptom severity, or antipsychotic dose. Conclusions and Relevance Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.

Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study.

Abstract: Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study

Mechanisms Underlying Psychosis and Antipsychotic Treatment Response in Schizophrenia: Insights from PET and SPECT Imaging

Abstract: Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo- a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal 'therapeutic window' for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.

Anatomically distinct dopamine release during anticipation and experience of peak emotion to music

Abstract: Music, an abstract stimulus, can arouse feelings of euphoria and craving, similar to tangible rewards that involve the striatal dopaminergic system. Using the neurochemical specificity of [(11)C]raclopride positron emission tomography scanning, combined with psychophysiological measures of autonomic nervous system activity, we found endogenous dopamine release in the striatum at peak emotional arousal during music listening. To examine the time course of dopamine release, we used functional magnetic resonance imaging with the same stimuli and listeners, and found a functional dissociation: the caudate was more involved during the anticipation and the nucleus accumbens was more involved during the experience of peak emotional responses to music. These results indicate that intense pleasure in response to music can lead to dopamine release in the striatal system. Notably, the anticipation of an abstract reward can result in dopamine release in an anatomical pathway distinct from that associated with the peak pleasure itself. Our results help to explain why music is of such high value across all human societies.

The Psychosis High-Risk State: A Comprehensive State-of-the-Art Review

Abstract: Context During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. Objective To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. Data Sources Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. Study Selection and Data Extraction Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. Data Synthesis Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. Conclusions The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

The nature of dopamine dysfunction in schizophrenia and what this means for treatment

Abstract: Context Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D 2 receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. Objective To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies. Data Sources The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011. Study Selection A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function. Data Extraction Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. Data Synthesis There was a highly significant elevation (P 2/3 receptor availability (Cohen d = 0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used. Conclusions The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D 2/3 receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.