Risk factors and outcomes after interruption of sedation in subarachnoid hemorrhage (ROUTINE-SAH)-a retrospective cohort study.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) often necessitates prolonged sedation to manage elevated intracranial pressure (ICP) and to prevent secondary brain injury. Optimal timing and biomarkers for predicting adverse events (AEs) during interruption of sedation (IS) after prolonged sedation are not well established. To guide sedation management in aSAH, we aimed to explore the frequency, risk factors, and outcomes of IS in aSAH. Methods: In a retrospective cohort study, a total of 148 patients with aSAH from January 2015 to April 2020 were screened. In total, 30 patients accounting for 42 IS were included in the analysis. Adverse events (AEs) during IS were used as core outcome measures and were categorized into neurological and non-neurological AEs. Baseline characteristics, clinical parameters before IS, AEs, and functional outcomes were collected using health records. Statistical analysis used generalized linear mixed-effects models with regularization to identify candidate predictors with subsequent bootstrapping to test model stability. As an exploratory analysis, multivariate linear and logistic regression was used to analyze the association between IS and intensive care unit length of stay, duration of mechanical ventilation, and functional outcomes. Results: The mean age was 56.9 (SD 14.8) years, and a majority of the patients presented with poor-grade SAH (16/30, 53.3%). Neurological and non-neurological AEs occurred in 60.0% (18/30) of the patients. Timing, number of IS attempts, ICP burden, craniectomy status, level of consciousness, heart rate, cerebral perfusion pressure, oxygen saturation, fraction of inspired oxygen, and temperature were selected as candidate predictors. Through bootstrapping, elapsed time since disease onset (OR 0.85, 95% confidence interval (95% CI) 0.75-0.97), ICP burden (OR 1.24, 95% CI 1.02-1.52), craniectomy (OR 0.68, 95% CI 0.48-0.69), and oxygen saturation (OR, 0.80 0.72-0.89) were revealed as relevant biomarkers for neurological AEs, while none of the pre-selected predictors was robustly associated with non-neurological AEs. Conclusion: In aSAH, complications during the definite withdrawal of sedation are frequent but can potentially be predicted using clinical parameters available at the bedside. Prospective multicenter studies are essential to validate these results and further investigate the impact of IS complications.

Fingernail Cortisol: A Biological Signal of Lifetime Major Depressive Disorder.

INTRODUCTION: Elevated levels of the hypothalamic-pituitary-adrenal axis hormone cortisol are a frequently replicated finding in major depressive disorder (MDD). However, the current state of research is inconclusive as to whether hypercortisolism represents a trait- or state-like biological signal of MDD. The aim of the present study was to investigate, for the first time, whether cortisol in fingernails, a highly accessible tissue, could distinguish currently remitted individuals with MDD from healthy controls. A further aim was to identify potential confounders of nail cortisol. METHODS: A total of N = 100 individuals from the general population were recruited. A structured clinical interview was administered, which resulted in two groups: n = 48 with lifetime MDD and n = 52 healthy controls. All participants answered questions on sociodemographic, lifestyle, and psychosocial characteristics. They also grew their nails for 14 days and cut them for the subsequent determination of cortisol. RESULTS: The groups differed in their nail cortisol concentrations, such that the individuals with lifetime MDD had significantly higher concentrations than the healthy controls (p = 0.041). Within the group of individuals with lifetime MDD, the number of experienced episodes was significantly correlated with cortisol (p = 0.011). Income emerged as the only significant confounder of cortisol (p = 0.008). CONCLUSION: Elevated fingernail cortisol appears to be a biological signal of MDD, even in the absence of a current major depressive episode. Its high accessibility and robustness render it a promising methodology for remote research as well as for the integration of biomarkers into clinical research and practice.

Cortisol response to traumatic stress to predict PTSD symptom development - a systematic review and meta-analysis of experimental studies.

Background: Pre-and post-traumatic hypothalamic-pituitary-adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events.Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms.Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (dSMC) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms.Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (kobservations = 25, dSMC = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = -.18 [-.35; -.01]), higher state happiness (k = 8, r = -.34 [-.59; -.03], variable inverted) and lower state anger (k = 9, r = -.14 [-.26; -.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = -.20 [-.33; -.06]) and lower state sadness (k = 17, r = -.16 [-.25; -.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]).Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms.

Experimental trauma paradigms successfully induced a cortisol response.Cortisol was predictive for single state, emotion-related symptoms, but not overall PTSD symptoms.Trauma paradigms shed light into the immediate post-trauma period that is hard to capture in real life, but the gap between experimental and naturalistic settings is difficult to overcome.

The effect of an internet-based intervention for depression on cortisol and alpha-amylase.

INTRODUCTION: Psychotherapeutic interventions for major depressive disorder (MDD) have been suggested to be associated with a normalization of biological stress system (i.e., the hypothalamic-pituitary-adrenal axis and the autonomic nervous system) dysregulation. Furthermore, pre-intervention cortisol parameters have been identified as prescriptive biological markers of treatment success. However, evidence of treatment effects on the biological stress systems is still sparse, and results are heterogeneous. The current study examined the effect of an internet-based intervention for MDD on salivary cortisol and alpha-amylase as well as hair cortisol concentrations. Moreover, the prescriptive capacity of pre-intervention cortisol and alpha-amylase concentrations on treatment response was explored. METHODS: Thirty-eight participants suffering from mild to moderate MDD collected saliva and hair samples throughout the intervention. Biological outcome parameters were salivary cortisol and alpha-amylase (awakening response, total diurnal output, diurnal slope) and hair cortisol concentrations. Treatment response was indicated by change in depression severity and perceived chronic stress. RESULTS: Treatment response on depression scores or chronic stress was not associated with changes in any of the cortisol or alpha-amylase parameters. Exploratory analysis indicated that non-responders showed a steeper alpha-amylase slope pre-intervention. DISCUSSION: The results indicate that changes in depressive symptoms did not correspond to changes of the biological stress systems, contradicting the suggested normalization of dysregulated hypothalamic-pituitary-adrenal axis or autonomic nervous system activity through a psychotherapeutic intervention. However, the results point to a potential role of pre-intervention alpha-amylase slope as a prescriptive marker of treatment response for depression.

Biological markers in clinical psychological research - A systematic framework applied to HPA axis regulation in PTSD.

Biological markers, particularly endocrine measurements, are increasingly being integrated into clinical psychological research. We introduce a systematic framework that classifies different functions of such biomarkers. The framework distinguishes between diagnostic biomarkers which add a biological perspective to conventional clinical assessments, prognostic biomarkers that inform about an individual's risk to develop or maintain a mental health disorder, and intervention-related biomarkers. Regarding interventions, including prevention and treatment, it further distinguishes between prescriptive biomarkers which predict an individual's response to an intervention, outcome biomarkers which evaluate intervention-related changes on a biological level and indicators of change mechanisms. We demonstrate how to apply the framework by exemplarily classifying and describing previously published systematic reviews and primary empirical studies on endogenous, peripheral cortisol concentrations as a biomarker for posttraumatic stress disorder (PTSD). The evidence on cortisol's diagnostic and prognostic value is heterogeneous and still sparse regarding parameters based on multiple cortisol measurements, such as the cortisol awakening response. With regard to interventions, most research focused on trauma-focused psychotherapy and cortisol reactivity to trauma reminders. This field of research appears to be growing and very promising due to its potential to optimize PTSD-related interventions. The proposed framework can help in gaining a systematic overview of existing research. It can assist in structuring, comparing, summarizing and evaluating empirical studies, and in identifying research gaps.

The Cortisol Assessment List (CoAL) A tool to systematically document and evaluate cortisol assessment in blood, urine and saliva.

Background: The reliable assessment of cortisol is a necessary requirement to produce replicable research. Several recommendations to increase cortisol assessment reliability exist. However, cortisol assessment methodology is still rather heterogeneous. For this reason, the Cortisol Assessment List (CoAL) was created.The CoAL can be used to guide researchers during the planning phase and document which measures were taken to increase cortisol data reliability in original studies. Moreover, the CoAL can be used to evaluate data quality in meta research. The items representing strategies to obtain reliable cortisol data can be weighted to indicate which are absolutely necessary to consider and which could be applied less restrictively in order to balance data quality and feasibility. In this paper, the construction process of the CoAL is described. Methods: Item synthesis of the CoAL included a literature search to extract empirically based suggestions regarding the reliable assessment of cortisol. Estimates for the item weighting system were obtained by inviting experts in the field to participate in an online survey (n = 25). Inter-rater reliability (IRR) of the CoAL, was determined by letting independent raters use the CoAL to evaluate a set of randomly selected original studies (k = 90). Results: The CoAL was divided into four subscales related to the reporting of sampling procedures, the consideration of state covariates, trait covariates and exclusion criteria. Survey results indicated high agreement among experts for most items (89%) with approximately half of the items in the CoAL being classified as necessary (Cortisol Awakening Response (CAR): 52%; basal cortisol: 52%; reactive cortisol: 44%) in order to obtain reliable cortisol data. Inter-rater agreement was very high (Cohen's Kappa = .98 - 0.99), indicating sufficient psychometric quality of the CoAL. Discussion: The CoAL is the first tool to systematically plan, document and evaluate cortisol assessment. The survey results indicate that the majority of respondents are aware of essential requirements to increase data reliability. However, results were heterogeneous for some items, highlighting the need to start a process of developing a broad scientific consensus regarding reliable cortisol assessment. The implementation of the CoAL could be a first step in this direction. In conclusion, the CoAL reflects empirical evidence and expert knowledge regarding cortisol assessment and can be used as a flexible tool to plan and document empirical studies or evaluate cortisol data quality in meta research.

Open and reproducible science practices in psychoneuroendocrinology: Opportunities to foster scientific progress.

This perspective article was written by invitation of the editors in chief as a summary and extension of the symposium entitled Psychoneuroendocrine Research in the Era of the Replication Crisis which was held at the virtual meeting of the International Society of Psychoneuroendocrinology 2021. It highlights the opportunities presented by the application of open and reproducible scientific practices in psychoneuroendocrinology (PNE), an interdisciplinary field at the intersection of psychology, endocrinology, immunology, neurology, and psychiatry. It conveys an introduction to the topics preregistration, registered reports, quantifying the impact of equally-well justifiable analysis decisions, and open data and scripts, while emphasizing 'selfish' reasons to adopt such practices as individual researcher. Complementary to the call for adoption of open science practices, we highlight the need for methodological best practice guidelines in the field of PNE, which could further contribute to enhancing replicability of results. We propose concrete steps for future actions and provide links to additional resources for those interested in adopting open and reproducible science practices in future studies.

Trauma exposure, posttraumatic stress disorder and oxytocin: A meta-analytic investigation of endogenous concentrations and receptor genotype.

Oxytocin's stress-reducing and social functions suggest an involvement in trauma processing and posttraumatic stress disorder (PTSD). We searched PubMed, PubPsych, PsycINFO, PsycARTICLES, Web of Science, ProQuest and ClinicalTrials.gov for studies assessing endogenous oxytocin, oxytocin receptor genotype or methylation in traumatized humans. Eligible studies (k = 66) were systematically described. We meta-analytically compared oxytocin parameters between traumatized and non-traumatized individuals (k = 17) and individuals with and without PTSD (k = 8), and correlated oxytocin with trauma exposure (k = 16) and PTSD symptoms (k = 8). Endogenous oxytocin concentrations did not differ between PTSD patients and healthy individuals. The remaining effects on endogenous oxytocin were heterogeneous. Subgroup analyses identified sampling-related, trauma-related and demographic moderators, resulting in inconsistent or non-significant effects. Methylation data were insufficient for meta-analyses, and meta-analytic genotype results were inconsistent. Unstimulated endogenous oxytocin was not a biomarker for trauma exposure or PTSD. Given the impact of methodology, more basic research on endogenous oxytocin measurements is needed. Future studies might consider the oxytocin stress response and investigate oxytocin longitudinally.

Demographic, sampling- and assay-related confounders of endogenous oxytocin concentrations: A systematic review and meta-analysis.

Studies on endogenous oxytocin concentrations are often criticized for the debatable comparability between specimens and the variation in reported values. We performed meta-regressions on k = 229 studies (n = 12 741 participants), testing whether specimen, extraction, sex, age, time of day, or fasting instructions influenced oxytocin measurements. Predicted oxytocin concentrations differed depending on specimen and extraction: Measurements were extremely high in unextracted blood, compared to extracted blood and other specimens. Measurements were higher in samples with more female participants and higher age. Instructions not to smoke before sampling were correlated with higher oxytocin in unextracted samples. There was no impact of instructions to refrain from eating, drinking, consume caffeine, alcohol or exercising. Oxytocin concentrations increased from morning to afternoon. Our results showed that oxytocin is differentially reflected in blood, saliva, urine and cerebrospinal fluid. Extraction impacts oxytocin measurements, particularly in blood. Considering relevant confounders might increase comparability between studies.

HPA axis regulation in posttraumatic stress disorder: A meta-analysis focusing on potential moderators.

Posttraumatic stress disorder (PTSD) is often associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Previous findings are inconsistent, possibly due to trauma exposure of controls or different hormone measurement methods. We investigated cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) in adults with clinical PTSD under basal or challenged conditions (Prospero registration no. CRD42016041690). A search of PubMed, Scopus, Medline, PsycINFO, Pilots/ProQuest, and Web of Science resulted in 108 included studies (N = 6484). Morning and 24 h cortisol were significantly lower in PTSD than in controls (g = -0.21; 95% CI: -0.42-(-0.01); g = -0.31; CI: -0.60-(-0.03)). Significant cortisol increases occurred after awakening in PTSD (g = 0.40; CI: 0.13-0.67) and in non-exposed controls (g = 0.96; CI: 0.59-1.33). Evening DHEA was significantly higher in PTSD than in non-exposed controls (g = 0.58; CI: 0.17-0.99). All groups showed large cortisol suppression effects after dexamethasone administration. Overall, the potential moderators investigated did not reveal a consistent pattern of HPA alterations.

The endogenous oxytocin system in depressive disorders: A systematic review and meta-analysis.

The oxytocin system is involved in psychological functions and interacts with biological systems that are altered in patients suffering from depressive disorders. This suggests a possible role of oxytocin in the development and maintenance of depression. We provide the first systematic review and meta-analysis that specifically addresses differences in basal endogenous oxytocin concentrations between patients with depressive disorders and healthy controls. A systematic literature search was conducted to identify studies that measured basal endogenous oxytocin concentrations in depressive patients and healthy controls. We included k = 13 studies (n = 368 patients and n = 346 healthy controls) in the qualitative review and k = 9 studies (n = 273 patients and n = 273 healthy controls) in the meta-analytic procedure. Standardized mean group differences were non-significant (g = -0.02, CI = [-0.41; 0.36]), indicating that depressive patients and healthy controls did not differ in basal endogenous oxytocin concentrations. The overall effect was heterogeneous. Effects within studies showing comparable risks of biases, as rated according to the Newcastle-Ottawa Quality Assessment Scale, were non-significant as well, but homogeneous. The findings suggest that more complex research designs and methodological approaches should be employed to detect and understand a possible role of the oxytocin system in depressive disorders. We provide recommendations for subsequent promising study designs, involving the consideration of illness phase, comorbidities and correlations with psychological functions or symptoms. We point out the strengths of reactivity designs and multidimensional measurement approaches and recommend to linking future research questions to theories of depression.

Cortisol and alpha-amylase assessment in psychotherapeutic intervention studies: A systematic review.

Dysregulations of the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS), two of the most prominent stress-responsive systems, have been associated with the development and maintenance of various mental disorders. It has been suggested that these alterations might normalize in the course of psychotherapeutic interventions. We conducted a comprehensive review of psychotherapeutic intervention effects on HPA axis and ANS regulation in adult samples with mental disorders. We searched four databases for psychotherapeutic intervention studies with mentally ill patient samples, assessing cortisol and/or alpha-amylase before and after treatment. Study quality and confounder consideration within biomarker assessment were examined. Twenty-five studies were included. Psychotherapeutic interventions and biomarker assessment methodology varied substantially between studies. Accordingly, meta-analytical computations were deemed unfeasible. Study characteristics especially regarding cortisol and alpha-amylase assessment and analysis procedures were comprehensively reviewed. Study quality and biomarker confounder consideration ratings were mostly moderate to strong. Based on the results, we provide recommendations regarding intervention design and biomarker assessment methodology to increase comparability of psychotherapeutic treatment effects in future studies.