Sensitivity of cognitive function tests to acute hypoxia in healthy subjects: a systematic literature review

Acute exposure to hypoxia can lead to cognitive impairment. Therefore, hypoxia may become a safety concern for occupational or recreational settings at altitude. Cognitive tests are used as a tool to assess the degree to which hypoxia affects cognitive performance. However, so many different cognitive tests are used that comparing studies is challenging. This structured literature evaluation provides an overview of the different cognitive tests used to assess the effects of acute hypoxia on cognitive performance in healthy volunteers. Less frequently used similar cognitive tests were clustered and classified into domains. Subsequently, the different cognitive test clusters were compared for sensitivity to different levels of oxygen saturation. A total of 38 articles complied with the selection criteria, covering 86 different cognitive tests. The tests and clusters showed that the most consistent effects of acute hypoxia were found with the Stroop test (where 42% of studies demonstrated significant abnormalities). The most sensitive clusters were auditory/verbal memory: delayed recognition (83%); evoked potentials (60%); visual/spatial delayed recognition (50%); and sustained attention (47%). Attention tasks were not particularly sensitive to acute hypoxia (impairments in 0%-47% of studies). A significant hypoxia level-response relationship was found for the Stroop test (p = 0.001), as well as three clusters in the executive domain: inhibition (p = 0.034), reasoning/association (p = 0.019), and working memory (p = 0.024). This relationship shows a higher test sensitivity at more severe levels of hypoxia, predominantly below 80% saturation. No significant influence of barometric pressure could be identified in the limited number of studies where this was varied. This review suggests that complex and executive functions are particularly sensitive to hypoxia. Moreover, this literature evaluation provides the first step towards standardization of cognitive testing, which is crucial for a better understanding of the effects of acute hypoxia on cognition

PK/PD modeling of 5-hydroxytryptophan (5-HTP) challenge test with cortisol measurement in serum and saliva

This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5-hydroxytryptophan (5-HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5-HTP challenge studies in healthy volunteers were collected. Serum 5-HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5-HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5-HTP could be described using a one-compartment model with a transit compartment. The typical value for clearance was 20.40 L h(-1) and showed inter-study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5-HTP PD effect on cortisol data with a slope of 4.16 ng mL(-1) h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5-HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5-HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK-PD model.Stress-related psychiatric disorders across the life spa

Cannabidiol in anxiety research: a translational integration of preclinical and clinical studies

Introduction: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Guidelines to inform the study design of future human studies are however lacking. Aims: We aimed to determine the boundary conditions for anxiolytic effects of CBD in humans by integrating, both qualitatively and quantitatively, pharmacokinetic (PK) and pharmacodynamic (PD) (and subsidiary safety) data from preclinical and clinical studies. Methods: We conducted two systematic reviews in Pubmed and Embase up to August 2021, into PK and PD data of systemic CBD exposure in both humans and animals, which includes anxiolytic and potential side effects. Risk of bias was assessed for effects on anxiety outcomes (SYRCLE’s RoB tool [1] and Cochrane RoB 2.0 [2]), PK outcomes, and harm-related outcomes. A control group was an inclusion criterion in outcome studies across species. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool [3] for a translational integration of PK and PD data. Further, a meta-analysis, stratified by type of anxiety and using three-level random effects models, was conducted to investigate sources of heterogeneity of CBD effects on anxiety outcomes. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach [4] was used to rate the quality of the evidence. Results: We synthesized data from 87 articles with the IB-derisk tool. Most studies (70.3%) reported null effects of CBD on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiolytic effects of CBD seemed to be clustered in certain differential concentration ranges, which differed between species. Data from 61 articles were included in the meta-analysis. The overall pooled effects of CBD on anxiety differed significantly from zero, p≤.02. The effect was moderate to large for conditioned anxiety in animals, Hedge’s G=0.68, 95%CI[0.11, 1.26], moderate for unconditioned anxiety in animals, Hedge’s G=0.50, 95%CI[0.29, 0.70], and large for human experimental anxiety, Hedge’s G=0.79, 95%CI[0.28, 1.31]. In all cases, compared to placebo/vehicle, CBD exerted beneficial effects on anxiety outcomes. No severe adverse effects were reported. There was substantial heterogeneity between average effect sizes within studies, σ2w Conclusions: A straightforward recommendation for optimal dosing was not possible, because there was no consistent linear effect of CBD on anxiety reduction, and concentration-effect relations were variable across species. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations. The low quality meta-analytic evidence confirmed the often discussed potential of CBD for treating anxiety symptoms. The compound induced anxiolytic effects, regardless of the type of anxiety studied. Moderator analyses will be conducted to determine other sources of heterogeneity of CBD effects, such as type of anxiety test and anxiety outcome

Diminished Posterior Precuneus Connectivity with the Default Mode Network Differentiates Normal Aging from Alzheimer's Disease

Multivariate analysis of psychological dat

Biperiden challenge model in healthy elderly as proof-of-pharmacology tool: a randomized, placebo-controlled trial

Selective M-1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition-enhancing effects in early-phase clinical development in healthy subjects is difficult. A challenge with the M-1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M-1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo-controlled, 3-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (-2.1 percentage point in adaptive tracking [95%CI, -3.043 to -1.148], verbal memory (2-3 fewer words recalled [95%CI, -5.9 to -0.2]) and working memory (up to a 50-millisecond increase in the n-back task reaction time [95%CI, 21.854-77.882]) compared with placebo. The PK data were best fitted by a 2-compartment model and showed high interoccasion and intersubject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction time, n-back accuracy, and adaptive tracking. In conclusion, biperiden caused M-1 mAChR-related dose- and concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition-enhancing effects of new cholinergic compounds that are being developed.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Klinische aspecten van ecstasy-gebruik (deel B): neuropsychiatrische effecten.

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Klinische aspecten van ecstasy-gebruik (deel A): neurofarmacologische effecten.

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The impact of the global COVID-19 pandemic on the conduct of clinical trials: Return to normalcy by considering the practical impact of a structured ethical analysis

During the outbreak of the COVID-19 pandemic many clinical trials were abruptly halted. Measures to contain the pandemic are currently taking effect and societies in general and healthcare systems in particular are considering how to return to normalcy. This opens up the discussion when and how clinical trials should be restarted while the COVID-19 pandemic has not yet resolved, and what should happen in case of a resurgence of the virus in the coming months. This article uses the four ethical principles framework as a structured approach to come to a set of practical, ethically grounded guidelines for halting and relaunching clinical trials during the COVID-19 pandemic. The framework applied provides a structured approach for all clinical trials stakeholders and thereby prevents unclear reasoning in a complex situation. While it is essential to prevent the virus from resurging and focus on developing a COVID-19 treatment as soon as possible, it is just as important to our society that we continue developing new drugs for other conditions. In this article we argue that the situation for clinical trials is not essentially different from the pre-COVID-19 era and that an overcautious approach will have negative consequences.Stress-related psychiatric disorders across the life spa