Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype

Low-grade peripheral inflammation is often present in psychotic patients. Toll-like receptors (TLRs) are pattern-recognition molecules that initiate inflammation. Our objective was to investigate the peripheral TLR activity in psychosis. Forty schizophrenia patients, twenty bipolar patients and forty healthy controls (HC) were recruited. Donated whole blood was cultured with TLR agonists for 24 h. Cell supernatants were analysed using a multiplex enzyme-linked immunosorbent assay approach to measure IL-1β, IL-6, IL-8 and tumour necrosis factor-α (TNFα). Plasma was analysed for cytokines, cortisol and acute phase proteins. Here, we show that selective TLR agonist-induced cytokine (IL-1β, IL-6, IL-8 and TNFα) release is enhanced in stimulated whole blood from schizophrenia and bipolar patients compared with HC. An exaggerated release of IL-1β, IL-6 and TNFα following treatment with the TLR2 agonist HKLM was detected in both disorders compared with controls. Enhanced TLR4-induced increases in IL-1β for both disorders coupled with TNFα increases for bipolar patients were observed. TLR8-induced increases in IL-1β for both disorders as well as IL-6 and TNFα increases for bipolar patients were detected. TLR9-induced increases in IL-8 for schizophrenia patients were also observed. No differences in TLR1, TLR3, TLR5, TLR6 or TLR7 activity were detected. Plasma levels of IL-6 were significantly elevated in bipolar patients while TNFα levels were significantly elevated in schizophrenia patients compared with controls. Plasma acute phase proteins were significantly elevated in bipolar patients. These data demonstrate that specific alterations in TLR agonist-mediated cytokine release contribute to the evidence of immune dysfunction in psychotic disorders

Ethics in clinical trial regulation: ethically relevant issues from EMA inspection reports

Background: Within the EU, regulators are obliged to take ethical issues into consideration during marketing authorization deliberation. The goal of this manuscript is to identify what kinds of ethical issues regulators encounter during marketing authorization application deliberations, and the incidence of these ethical issues. Methods: This study used an EMA-provided Excel file that contains all the GCP non-compliance findings from all inspection reports from 2008–2012. There were 112 medicinal products and a total of 288 clinical trial sites. There were a total of 4014 GCP non-compliance findings. The findings that were ethically relevant were extracted using NVivo 10.0 and categories for the ethically relevant findings (ERFs) were created. Note was taken of the incidence of ERFs for each category and the inspectors’ gradings of these findings were extracted. This study also looked at the mean and the maximum number of ERFs per grading per medicinal product application, as well as the number of medicinal products with at least one ERF and those with at least major ERFs. Results: With multiple coding, there were 1685 ERFs. ERFs were present in almost all of the medicinal products (97.3%). The majority of ERFs were graded as major. At least major ERFs were present in almost all medicinal products with ERFs. The categories with the highest number of ERFs were protocol issues, patient safety, and professionalism issues. In terms of the density of combined critical and major findings, monitoring and oversight, protocol issues, and respect for persons top the list. This study also showed that, on average, there were 7.54 major and 2.95 critical ERFs per medicinal product application, although ERFs can increase to 30 major and 12 critical. Conclusion: Regulators regularly encounter ERFs that at least “might adversely affect the rights, safety or well-being of the subjects”. It remains to be explored how regulators respond to these ethical issues