Abstract
BackgroundPsychosis is seen in a number of disorders and treated with the same drugs. However, there is considerable variability in response to treatment and clinical course. Understanding the neurobiology underlying psychosis across diagnoses and in treatment response is important to help guide the development of new treatments and biomarkers for treatment response. Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders.MethodsTwo cohorts of first episode patients, one with a diagnosis of schizophrenia (n=16) and another with a diagnosis of bipolar affective disorder (n=22) received 18F-DOPA PET and [1H]-MR spectroscopy imaging and clinical measures. All patients had experienced a psychotic episode and received clinical follow-up over 18 months to determine diagnostic stability. We then conducted a meta-analysis using a novel meta-analytic approach to quantify variability in measures to investigate structural and neurochemical heterogeneity in schizophrenia and bipolar affective disorder. The entire PubMed, EMBase and PsychInfo databases were searched from inception to identify relevant studies and the natural log of the measures of dispersion and the coefficient of variance.ResultsStriatal dopamine synthesis capacity (Kicer) was significantly elevated in both bipolar (effect size=1.02; p<0.003) and schizophrenia (effect size=0.9; p<0.05) groups, compared to controls. There was no significant difference in dopamine synthesis capacity between bipolar and schizophrenia groups (p>0.4). Kicer was significantly positively correlated with positive psychotic symptom severity in the transdiagnostic group of people with psychosis (r=0.52, p<0.004), and in the bipolar group after adjusting for manic symptom severity (r=0.6, p<0.01). There were no differences in glutamate levels in the anterior cingulate cortex.In the meta-analyses a total of 128 studies were identified including >4000 patients and >4000 controls. Variability ratio was significantly increased in patients relative to controls in gray matter volumes in temporal lobe (VR=1.1, p=0.004) and thalamus (VR=1.16, p<0.001), and in striatal dopamine receptor density (p<0.05) but unaltered in frontal cortex and significantly reduced in the anterior cingulate cortex (VR=0.9, p=0.02)DiscussionElevated dopamine synthesis capacity is associated with psychosis across diagnostic boundaries and linked to the severity of psychotic symptoms, even after adjusting for manic symptom severity. Striatal dopamine receptor density and structural gray matter volumes in a number of cortical and sub-cortical regions show heterogeneity in psychotic disorders, but frontal cortical regions show unaltered and, in the case of the anterior cingulate cortex, reduced heterogeneity, suggesting alterations are homogenous across patients. Taken together these findings striatal dopamine synthesis and structural changes in frontal cortex are common mechanisms linked to psychosis across disorders.
Highlights
Recent genomic studies have begun to reveal the genetic architecture of psychiatric disorder and to give important insights into the relationship between the psychiatric syndromes that form the basis of current taxonomy
I will present genomic data, predominantly from the study of rare variants, that support the idea of a neurodevelopmental continuum, in which schizophrenia and bipolar disorder, together with childhood neurodevelopmental disorders, such as ID, ASD and ADHD represent the diverse range of outcomes that follow from disrupted or deviant brain development and that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: ID, ASD, schizophrenia and bipolar disorder
Elevated dopamine synthesis and release capacity and structural brain changes have been consistently associated with schizophrenia, but it remains unknown how variable these are, or how they compare across psychotic disorders
Summary
Downloaded from https://academic.oup.com/schizophreniabulletin/article/44/suppl_1/S13/4957095 by guest on 23 December 2021 at risk of autism), showing that there are common dopaminergic alterations linked to psychosis across disorders, as well as showing that structural and neurochemical brain heterogeneity is increased in most brain regions, but also identifying key cortical and sub-cortical regions with increased homogeneity. Dr Clementz, USA, will present new EEG and cognitive data from over 400 patients with schizophrenia, and bipolar disorder. This shows differences in intrinsic neural activity that cuts across diagnoses, identifying subtypes that were linked to differences in cognitive functioning. Dr Wichers, Netherlands, will present new data from a longitudinal study of adolescents using in-depth real-time phenotyping using experience sampling to investigate the relationship between the coherence of responses and the subsequent development of psychotic and other symptom domains one year later. Her novel application of complex systems theory identifies suspiciousness as a common predictor of the later development of a number of symptoms, but also that other responses, such as low mood, determine the specificity of later outcomes to psychosis. Overall this symposium will bring together researchers using different, complementary approaches to provide a comprehensive and multi-disciplinary analysis. By bringing researchers from different disciplines together it will enable common mechanisms to be considered, and new insights to be developed. Finally, Dr DeLisi’s wide-reaching experience means she is well placed to lead the discussion of the implications of these findings for understanding the neurobiology of schizophrenia, and for biomarker development as well as considering their implications for the developing new treatments. The symposium includes gender diversity in presenters and chairs, speakers from multiple institutions across continents, and diversity in career levels with speakers from early, mid and established positions.
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