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Schizophrenia is a chronic mental illness that affects up to 1% of the population. While efficacious therapies are available for positive symptoms, effective treatment of cognitive and negative symptoms remains an unmet need after decades of research. New developments in the field of neuroimaging are accelerating our knowledge gain regarding the underlying pathophysiology of symptoms in schizophrenia and psychosis spectrum disorders, inspiring new targets for drug development. However, no validated and qualified biomarkers are currently available to support the development of new therapeutics. This review summarizes the current use of neuroimaging technology in clinical drug development for psychotic disorders. As exemplified by drug development programs that target NMDA receptor hypofunction, neuroimaging results play a critical role in target discovery and establishing target engagement and dose selection. Furthermore, pharmacological neuroimaging may provide response biomarkers that allow for early decision making in proof-of-concept studies that leverage pharmacological challenge models in healthy volunteers. That said, while response and predictive biomarkers are starting to be evaluated in patient populations, they continue to play a limited role. Novel approaches to neuroimaging data acquisition and analysis may aid the establishment of biomarkers that are predictive at the individual level in the future. Nevertheless, various gaps in knowledge need to be addressed and biomarkers need to be validated to establish them as "fit for purpose" in drug development., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aims: The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types., Methods: This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO 2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types., Results: In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68 μV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73 μV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2 μV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54 μV; 95% CI -6.21, -2.87) and pregabalin (-3.72 μV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78 μV; 95% CI -5.31, -2.25) and duloxetine (-2.32 μV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings., Conclusions: LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development., (© 2017 The British Pharmacological Society.)

Introduction: Remifentanil is an opioid with a unique pharmacokinetic profile. Its organ-independent elimination and short context-sensitive half time of 3 to 4 minutes lead to a highly predictable offset of action. We tested the hypothesis that with an analgesia-based sedation regimen with remifentanil and propofol, patients after cardiac surgery reach predefined criteria for discharge from the intensive care unit (ICU) sooner, resulting in shorter duration of time spent in the ICU, compared to a conventional regimen consisting of midazolam and fentanyl. In addition, the two regimens were compared regarding their costs., Methods: In this prospective, open-label, randomised, single-centre study, a total of 80 patients (18 to 75 years old), who had undergone cardiac surgery, were postoperatively assigned to one of two treatment regimens for sedation in the ICU for 12 to 72 hours. Patients in the remifentanil/propofol group received remifentanil (6- max. 60 microg kg(-1) h(-1); dose exceeds recommended labelling). Propofol (0.5 to 4.0 mg kg(-1) h(-1)) was supplemented only in the case of insufficient sedation at maximal remifentanil dose. Patients in the midazolam/fentanyl group received midazolam (0.02 to 0.2 mg kg(-1) h(-1)) and fentanyl (1.0 to 7.0 microg kg(-1) h(-1)). For treatment of pain after extubation, both groups received morphine and/or non-opioid analgesics., Results: The time intervals (mean values +/- standard deviation) from arrival at the ICU until extubation (20.7 +/- 5.2 hours versus 24.2 h +/- 7.0 hours) and from arrival until eligible discharge from the ICU (46.1 +/- 22.0 hours versus 62.4 +/- 27.2 hours) were significantly (p < 0.05) shorter in the remifentanil/propofol group. Overall costs of the ICU stay per patient were equal (approximately euro1,700 on average)., Conclusion: Compared with midazolam/fentanyl, a remifentanil-based regimen for analgesia and sedation supplemented with propofol significantly reduced the time on mechanical ventilation and allowed earlier discharge from the ICU, at equal overall costs.

The role of lipid peroxidation after brain injury is still not completely understood, and results of different studies have been equivocal. In this study, three proposed peroxidation markers were determined in patients early after isolated head injury and results compared to healthy controls. Malondialdehyde (MDA) and thiobarbituric acid-reactive substances (TBARS) were measured in plasma, and n-pentane was determined in patients' exhaled air. For MDA and TBARS no significant differences could be shown (0.267 vs. 0.358 ng/mL, and 0.896 vs. 0.814 ng/mL in patients vs. healthy volunteers, respectively). n-Pentane, however, was significantly increased in the expired air of patients (0.471 vs. 0.118 nmol/L in healthy volunteers). Similar results for n-pentane were obtained when only male patients and volunteers were considered (0.510 vs. 0.113 nmol/L). Stratification according to clinical outcome showed significantly higher values for n-pentane in male patients with poor outcome (0.656 nmol/L) in comparison with healthy male volunteers (0.113 nmol/L). No difference was found when patients were stratified according to the presence or absence of subarachnoid hemorrhage. It is concluded that, only in a sub-population of patients with brain injury, lipid-peroxidation is a crucial mechanism. n-Pentane seems to be a valuable marker to detect lipid peroxidation early after brain trauma. Malondialdehyde may be of value only later in the course of the disease. TBARS are not a specific marker and should therefore not be used.

Free radical-mediated inflammatory processes account for a great portion of morbidity and mortality in critically ill patients. The purpose of this study was to determine two plasma peroxidation markers and three volatile markers related to lipid peroxidation, metabolic activity and cholesterol metabolism, and to explore relationships between the different markers and patients' clinical status. Substances were analyzed in whole blood and in exhaled air in patients with head injury, acute respiratory distress syndrome (ARDS) and in those being at risk of developing ARDS. These results were compared with the baseline measurements in healthy individuals. Additionally, patients were assessed according to their inflammatory status. Concentrations of malondialdehyde and thiobarbituric acid-reactive substances in plasma as well as pentane concentrations in breath increased with increasing inflammatory status. Although these compounds are generated through peroxidation of fatty acids, concentrations of these markers were significantly different in patient groups. Isoprene concentrations were lowest in the ARDS group. Acetone concentrations were not different between patient groups. We conclude that for the assessment of lipid peroxidation and other inflammatory reactions a set of parameters has to be defined. More detailed insights into inflammatory processes can be obtained when the volatile markers and the serum markers are considered together.