Phospholipids and insulin resistance in psychosis : a lipidomics study of twin pairs discordant for schizophrenia

BACKGROUND: Several theories have been proposed to conceptualize the pathological processes inherent to schizophrenia. The "prostaglandin deficiency" hypothesis postulates that defective enzyme systems converting essential fatty acids to prostaglandins lead to diminished levels of prostaglandins, which in turn affect synaptic transmission. METHODS: Herein we sought to determine the lipidomic profiles associated with schizophrenia in twin pairs discordant for schizophrenia as well as unaffected twin pairs. The study included serum samples from 19 twin pairs discordant for schizophrenia (mean age 51 +/- 10 years; 7 monozygotic pairs; 13 female pairs) and 34 age and gender matched healthy twins as controls. Neurocognitive assessment data and gray matter density measurements taken from high-resolution magnetic resonance images were also obtained. Lipidomics platform using Ultra Performance Liquid Chromatography coupled to time-of-flight mass spectrometry was applied for the analysis of serum samples. RESULTS: In comparison to their healthy co-twins, the patients had elevated triglycerides and were more insulin resistant. They had diminished lysophosphatidylcholine levels which associated with decreased cognitive speed. CONCLUSIONS: Our findings may be of pathophysiological relevance since lysophosphatidylcholines, byproducts of phospholipase A2-catalyzed phospholipid hydrolysis, are preferred carriers of polyunsaturated fatty acids across the blood-brain barrier. Furthermore, diminishment of lysophosphatidylcholines suggests that subjects at risk of schizophrenia may be more susceptible to infections. Their association with cognitive speed supports the view that altered neurotransmission in schizophrenia may be in part mediated by reactive lipids such as prostaglandins.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Disruption in peripheral expression of genes related to cognition among patients with schizophrenia and bipolar disorder and their co-twins

Schizophrenia and bipolar disorder are substantially heritable psychiatric illnesses. This study examined peripheral gene expression in an initial sample recruited in Sweden consisting of 35 individuals with schizophrenia and their unaffected co-twins, 24 individuals with bipolar disorder and their unaffected co-twins, and 60 control twins without a history of significant psychiatric illness. Results were confirmed with a secondary sample of 18 individuals with schizophrenia and their unaffected co-twins and 37 non-psychiatric control twins recruited in Finland. Expression in peripheral blood lymphocytes was measured using the Illumina Human WG6 v3.0 gene chip. A cognitive endophenotype was used to screen for genes that varied in relation to cognition out of the genome-wide panel. Results of the mixed-model ANOVA revealed 28 genes showed a significant association with cognitive performance at a corrected α = 0.05 and 47 at a corrected α = 0.10. Twelve of these genes showed significantly decreased expression in patients with schizophrenia and five showed decreased expression in patients with bipolar disorder compared to controls. Nine genes also showed decreased expression in the unaffected co-twins of patients with schizophrenia compared to controls. All twelve genes also showed decreased expression in the secondary sample of patients with schizophrenia. Further research is necessary to determine the relationship between decreased peripheral expression of these genes and expression levels in the central nervous system and relationships with other factors such as duration of illness and psychotropic medication use

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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