ORCID Profile
0000-0003-0194-0806
Current Organisation
South London and Maudsley NHS Foundation Trust
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Publisher: SAGE Publications
Date: 09-2022
DOI: 10.1177/02698811221099643
Abstract: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippoc us in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling however, this has not been tested in vivo. In this study, we investigated the relationship between hippoc al NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippoc al NMDAR availability using the PET ligand [ 18 F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy ( 1 H-MRS). A total of 33 in iduals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippoc al DVR and striatal glutamate levels in people with first-episode psychosis (rho = −0.74, p 0.001) but not in healthy controls (rho = −0.22, p = 0.44). This study show that lower relative NMDAR availability in the hippoc us may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.NEUROPHARM.2019.107704
Abstract: Antipsychotic drugs are central to the treatment of schizophrenia and other psychotic disorders but are ineffective for some patients and associated with side-effects and nonadherence in others. We review the in vitro, pre-clinical, clinical and molecular imaging evidence on the mode of action of antipsychotics and their side-effects. This identifies the key role of striatal dopamine D2 receptor blockade for clinical response, but also for endocrine and motor side-effects, indicating a therapeutic window for D2 blockade. We consider how partial D2/3 receptor agonists fit within this framework, and the role of off-target effects of antipsychotics, particularly at serotonergic, histaminergic, cholinergic, and adrenergic receptors for efficacy and side-effects such as weight gain, sedation and dysphoria. We review the neurobiology of schizophrenia relevant to the mode of action of antipsychotics, and for the identification of new treatment targets. This shows elevated striatal dopamine synthesis and release capacity in dorsal regions of the striatum underlies the positive symptoms of psychosis and suggests reduced dopamine release in cortical regions contributes to cognitive and negative symptoms. Current drugs act downstream of the major dopamine abnormalities in schizophrenia, and potentially worsen cortical dopamine function. We consider new approaches including targeting dopamine synthesis and storage, autoreceptors, and trace amine receptors, and the cannabinoid, muscarinic, GABAergic and glutamatergic regulation of dopamine neurons, as well as post-synaptic modulation through phosphodiesterase inhibitors. Finally, we consider treatments for cognitive and negative symptoms such dopamine agonists, nicotinic agents and AMPA modulators before discussing immunological approaches which may be disease modifying. This article is part of the issue entitled 'Special Issue on Antipsychotics'.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.DRUGALCDEP.2015.08.021
Abstract: The current burden of cannabis-related presentations to emergency health services is largely unknown. This paper presents data collected over a 13-year period in metropolitan Melbourne, Australia as part of the Ambo Project, a unique surveillance system that analyses and codes paramedic records for drug-related trends and harms. Cannabis-related ambulance attendances involving 15-59 year olds in metropolitan Melbourne were analysed retrospectively from 2000 to 2013 (n=10,531). Trends and attendance characteristics were compared among cannabis only (CO)-, cannabis and alcohol (CA)- and cannabis with polydrug use (CP)-related attendances. Changes in alcohol and drug involvements in cannabis-related attendances were explored. Rates of cannabis-related ambulance attendances increased significantly over the study period. Increasing rate of attendances per 100,000 population per year changed from 0.6 (2000-2010) to 5.5 (2010-2013). This sharp change was driven by CO- and CP-related attendances (rate of CA-related attendance increased steadily). The highest increasing rate (15.6) was for CO-related attendances among 15-29 years old males (2010-2013). Crystal meth hetamine became the most common illicit co-intoxicant amongst cannabis presentations in 2013. Relative to the total drug-related burden on ambulance services, cannabis-related presentations appear to be a small but significant and increasing problem. Significant changes in trends across other drug involvement and demographic subgroups suggest a possible shift in the cannabis using population and/or a change in using behaviours. Public health strategies should raise awareness of the increased risk posed by cannabis polydrug use and high attendance subpopulations should be determined.
Publisher: Springer Science and Business Media LLC
Date: 12-09-2022
DOI: 10.1007/S00213-022-06216-3
Abstract: The pathophysiology of schizophrenia involves abnormal reward processing, thought to be due to disrupted striatal and dopaminergic function. Consistent with this hypothesis, functional magnetic resonance imaging (fMRI) studies using the monetary incentive delay (MID) task report hypoactivation in the striatum during reward anticipation in schizophrenia. Dopamine neuron activity is modulated by striatal GABAergic interneurons. GABAergic interneuron firing rates, in turn, are related to conductances in voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels, suggesting that targeting Kv3.1/3.2 could augment striatal function during reward processing. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on striatal activation in patients with schizophrenia, using the MID task. Each participant completed the MID during fMRI scanning on two occasions: once at baseline, and again following either 4 weeks of AUT00206 or placebo treatment. We found a significant inverse relationship at baseline between symptom severity and reward anticipation-related neural activation in the right associative striatum ( r = -0.461, p = 0.035). Following treatment with AUT00206, there was a significant increase in reward anticipation-related activation in the left associative striatum (t (13) = 4.23, peak-level p (FWE) 0.05)), but no significant effect in the ventral striatum. This provides preliminary evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address reward-related striatal abnormalities in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2019
DOI: 10.1007/S00702-019-02080-2
Abstract: Parvalbumin interneurons are fast-spiking GABAergic neurons that provide inhibitory control of cortical and subcortical circuits and are thought to be a key locus of the pathophysiology underlying schizophrenia. In view of the contradictory results regarding the nature of parvalbumin post-mortem findings in schizophrenia, we conducted a quantitative meta-analysis of the data on parvalbumin cell density and parvalbumin mRNA levels in pre-frontal regions in the brains of patients with schizophrenia ( n = 274) compared with healthy controls ( n = 275). The results suggest that parvalbumin interneurons are reduced in density in the frontal cortex of patients with schizophrenia ( Hedges’ g = − 0.27 p = 0.03) and there is a non-significant reduction in parvalbumin mRNA levels ( g = − 0.44 p = 0.12). However, certain methodological issues need to be considered in interpreting such results and are discussed in more detail. A meta-regression was conducted for post-mortem interval and year of publication as covariates which were both non-significant, except in the mRNA meta-analysis where post-mortem interval was found to be significant. Overall our findings provide tentative support for the hypothesis that the GABAergic system is deficient in schizophrenia and that parvalbumin-containing interneurons offer a potential target for treatment. However, further well-controlled studies that examine multiple regions and layers are warranted to determine whether parvalbumin alterations are region or layer specific and to test the robustness of the findings further.
Publisher: SAGE Publications
Date: 09-2022
DOI: 10.1177/02698811221122031
Abstract: Current treatments for schizophrenia act directly on dopamine (DA) receptors but are ineffective for many patients, highlighting the need to develop new treatment approaches. Striatal DA dysfunction, indexed using [ 18 F]-FDOPA imaging, is linked to the pathoetiology of schizophrenia. We evaluated the effect of a novel drug, AUT00206, a Kv3.1/3.2 potassium channel modulator, on dopaminergic function in schizophrenia and its relationship with symptom change. Additionally, we investigated the test–retest reliability of [ 18 F]-FDOPA PET in schizophrenia to determine its potential as a biomarker for drug discovery. Twenty patients with schizophrenia received symptom measures and [ 18 F]-FDOPA PET scans, before and after being randomised to AUT00206 or placebo groups for up to 28 days treatment. AUT00206 had no significant effect on DA synthesis capacity. However, there was a correlation between reduction in striatal dopamine synthesis capacity (indexed as Ki cer ) and reduction in symptoms, in the AUT00206 group ( r = 0.58, p = 0.03). This was not observed in the placebo group ( r = −0.15, p = 0.75), although the placebo group may have been underpowered to detect an effect. The intraclass correlation coefficients of [ 18 F]-FDOPA indices in the placebo group ranged from 0.83 to 0.93 across striatal regions. The relationship between reduction in DA synthesis capacity and improvement in symptoms in the AUT00206 group provides evidence for a pharmacodynamic effect of the Kv3 channel modulator. The lack of a significant overall reduction in DA synthesis capacity in the AUT00206 group could be due to variability and the low number of subjects in this study. These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [ 18 F]-FDOPA PET imaging showed very good test–retest reliability in patients with schizophrenia.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stephen Kaar.