Letter from the editorial board

Letter from the editorial board of MSJP

Letter from the Editorial Board

Letter from the Editorial Board of the MSJP

In-vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [¹¹C]<i>(R)</i>-PK11195 positron emission tomography study

Abstract Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [11C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared with healthy controls (mean difference 4%, P=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, P=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics

Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis

From Springer Nature via Jisc Publications RouterHistory: received 2020-01-06, rev-recd 2020-06-09, accepted 2020-06-18, registration 2020-06-19, pub-electronic 2020-06-30, online 2020-06-30, pub-print 2021-09Publication status: PublishedFunder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265; Grant(s): MR/K020803/1, MR/K020803/1, MR/K020803/1, MR/K020803/1, MR/K020803/1Abstract: Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving

Association of Common Polymorphisms in GLUT9 Gene with Gout but Not with Coronary Artery Disease in a Large Case-Control Study

BACKGROUND: Serum uric acid (UA) levels have recently been shown to be genetically influenced by common polymorphisms in the GLUT9 gene in two genome-wide association analyses of Italian and British populations. Elevated serum UA levels are often found in conjunction with the metabolic syndrome. Hyperuricemia is the major risk factor for gout and has been associated with increased cardiovascular morbidity and mortality. The aim of the present study was to further elucidate the association of polymorphisms in GLUT9 with gout and coronary artery disease (CAD) or myocardial infarction (MI). To test our hypotheses, we performed two large case-control association analyses of individuals from the German MI Family Study. METHODS AND FINDINGS: First, 665 patients with gout and 665 healthy controls, which were carefully matched for age and gender, were genotyped for four single nucleotide polymorphisms (SNPs) within or near the GLUT9 gene. All four SNPs demonstrated highly significant association with gout. SNP rs6855911, located within intron 7 of GLUT9, showed the strongest signal with a protective effect of the minor allele with an allelic odds ratio of 0.62 (95% confidence interval 0.52-0.75; p = 3.2*10(-7)). Importantly, this finding was not influenced by adjustment for components of the metabolic syndrome or intake of diuretics. Secondly, 1,473 cases with severe CAD or MI and 1,241 healthy controls were tested for the same four GLUT9 SNPs. The analyses revealed, however, no significant association with CAD or with MI. Additional screening of genome-wide association data sets showed no signal for CAD or MI within the GLUT9 gene region. CONCLUSION: Thus, our results provide compelling evidence that common genetic variations within the GLUT9 gene strongly influence the risk for gout but are unlikely to have a major effect on CAD or MI in a German population

Letter from the editors

Letter from the editors for Vol. 3 of the Maastricht Student Journal of Psychology and Neuroscienc

Acute and chronic changes in brain activity with deep brain stimulation for refractory depression

Deep brain stimulation is a potential option for patients with treatment-refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery–Asberg Depression Rating Scale score from baseline of ≥50%, and remission as a Montgomery–Asberg Depression Rating Scale score ≤8. Changes in regional cerebral blood flow were assessed using [15O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non-remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response.</jats:p