The Involvement of Hypothalamus–Pituitary–Adrenal (HPA) Axis in Suicide Risk

Stress and Hypothalamic–Pituitary–Adrenal (HPA) axis dysregulation play a major role in various pathophysiological processes associated with both mood disorders and suicidal behavior. We conducted a systematic review with the primary aim of clarifying the nature and extent of HPA axis activity and suicidal behavior. The second aim of this review was to investigate whether potential biomarkers related to HPA axis abnormalities act as individual susceptibility factors for suicide. The PRISMA statement for reporting systematic reviews was used. Only articles published in English peer-reviewed journals were considered for possible inclusion; we excluded case reports, meta-analyses, and systematic reviews, and studies that did not clearly report statistical analysis, diagnostic criteria, or the number of patients included. Overall, 36 articles on HPA axis and suicide risk met inclusion criteria and were reviewed. Studies that investigated tests detecting biomarkers and the role of early life stressors in suicide risk were also included. We found that HPA axis activity is involved in suicide risk, regardless of the presence or absence of psychiatric conditions. The HPA axis abnormalities, mainly characterized by hyperactivity of the HPA axis, may exert an important modulatory influence on suicide risk. Impaired stress response mechanisms contribute to suicide risk. Targeting HPA axis dysregulation might represent a fruitful strategy for identifying new treatment targets and improving suicide risk prediction.

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The Impact of Excluding Nonrandomized Studies From Systematic Reviews in Rare Diseases: “The Example of Meta-Analyses Evaluating the Efficacy and Safety of Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis”

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.690615 ◽

2021 ◽

Vol 8 ◽

Author(s):

Miguel Sampayo-Cordero ◽

Bernat Miguel-Huguet ◽

Andrea Malfettone ◽

José Manuel Pérez-García ◽

Antonio Llombart-Cussac ◽

...

Keyword(s):

Selection Bias ◽

Systematic Reviews ◽

Rare Diseases ◽

Case Reports ◽

Patient Characteristics ◽

Reference Population ◽

Enzyme Replacement ◽

Number Of Patients ◽

Meta Analyses ◽

The Impact

Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases.

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HPA axis dysregulation and suicidal behavior in depression – Differentiation of a genetically distinct subgroup?

Pharmacopsychiatry ◽

10.1055/s-2003-825457 ◽

2004 ◽

Vol 36 (05) ◽

Author(s):

A Pfennig ◽

HE Kuenzel ◽

N Kern ◽

B Fuchs ◽

J Brunner ◽

...

Keyword(s):

Hpa Axis ◽

Suicidal Behavior ◽

Distinct Subgroup ◽

Hpa Axis Dysregulation

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Stress, Cortisol and Suicide Risk

10.31234/osf.io/92b7z ◽

2019 ◽

Author(s):

Daryl Brian O'Connor

Keyword(s):

Risk Factors ◽

Suicidal Behavior ◽

Suicide Risk ◽

Stressful Events ◽

Additional Risk ◽

Global Health Issue ◽

History Of ◽

Hpa Axis Activity ◽

The Impact

Suicide is a global health issue accounting for at least 800,000 deaths per annum. Numerous models have been proposed that differ in their emphasis on the role of psychological, social, psychiatric and neurobiological factors in explaining suicide risk. Central to many models is a stress-diathesis component which states that suicidal behavior is the result of an interaction between acutely stressful events and a susceptibility to suicidal behavior (a diathesis). This article presents an overview of studies that demonstrate that stress and dysregulated hypothalamic-pituitary-adrenal (HPA) axis activity, as measured by cortisol levels, are important additional risk factors for suicide. Evidence for other putative stress-related suicide risk factors including childhood trauma, impaired executive function, impulsivity and disrupted sleep are considered together with the impact of family history of suicide, perinatal and epigenetic influences on suicide risk.

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Abordagem aos Doentes com Intolerância às Estatinas: Revisão Baseada na Evidência

Acta Médica Portuguesa ◽

10.20344/amp.10376 ◽

2020 ◽

Vol 33 (1) ◽

pp. 49 ◽

Cited By ~ 1

Author(s):

Joana Tendais Almeida ◽

Ana Luísa Esteves ◽

Filipa Martins ◽

Isabel Palma

Keyword(s):

Systematic Reviews ◽

Patient Adherence ◽

Management Strategies ◽

Lipid Lowering ◽

Lipid Lowering Therapy ◽

Level Of Evidence ◽

Mortality And Morbidity ◽

Number Of Patients ◽

Pubmed Database ◽

Meta Analyses

Introduction: Statins are among the most effective drugs in lowering cholesterol levels and, consequently, in reducing cardiovascular mortality and morbidity. Although generally well tolerated, they have adverse effects that may reduce patient adherence to therapy. The objective of this evidence-based review is to summarize the evidence on the effectiveness of alternative management strategies in patients with intolerance to statins.Material and Methods: A literature search including clinical practice guidelines, systematic reviews and meta-analyses was conducted, in January 2017, in major international databases, and considered articles published in the last 10 years. The search was complemented with research papers published over the past three years and found in the PubMed database. The level of evidence and strength of recommendation were determined using the scale Strength of Recommendation Taxonomy - SORT.Results: We included eight guidelines, six systematic reviews and one research paper.Discussion: The strategies proposed by the different studies vary according to the severity of symptoms of intolerance including maintenance of the statin therapy (dose reduction, addition of a statin of equal or lower intensity or alternate days’ uptake) and lipid-lowering therapy with other drugs (ezetimibe monotherapy or association with statin tolerated dose). Supplementation with coenzyme Q10 or vitamin D, in order to improve adherence to treatment with statins, is not recommended.Conclusion: This review highlights some alternatives to address patients’ intolerance to statins; however, these are mostly based on recommendations with low to moderate evidence. Therefore, further research with randomized studies involving greater number of patients is required, in order to obtain a more robust recommendation.

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Impact of heterogeneity and effect size on the estimation of the optimal information size: analysis of recently published meta-analyses

BMJ Open ◽

10.1136/bmjopen-2017-015888 ◽

2017 ◽

Vol 7 (11) ◽

pp. e015888 ◽

Cited By ~ 7

Author(s):

Josep M Garcia-Alamino ◽

Clare Bankhead ◽

Carl Heneghan ◽

Nicola Pidduck ◽

Rafael Perera

Keyword(s):

Systematic Reviews ◽

Effect Size ◽

Sequential Analysis ◽

Trial Sequential Analysis ◽

Size Analysis ◽

Cochrane Reviews ◽

Number Of Patients ◽

Optimal Information ◽

Meta Analyses ◽

The Impact

ObjectiveTo estimate the proportion of systematic reviews that meet the optimal information size (OIS) and assess the impact heterogeneity and effect size have on the OIS estimate by type of outcome (eg, mortality, semiobjective or subjective).MethodsWe carried out searches of Medline and Cochrane to retrieve meta-analyses published in systematic reviews from 2010 to 2012. We estimated the OIS usingTrial Sequential Analysissoftware (TSA V.0.9) and based on several heterogeneity and effect size scenarios, stratifying by type of outcome (mortality/semiobjective/subjective) and by Cochrane/non-Cochrane reviews.ResultsWe included 137 meta-analyses out of 218 (63%) potential systematic reviews (one meta-analysis from each systematic review). Of these reviews, 83 (61%) were Cochrane and 54 (39%) non-Cochrane. The Cochrane reviews included a mean of 6.5 (SD 6.1) studies and the non-Cochrane included a mean of 13.2 (SD 10.2) studies. The mean number of patients was 2619.1 (SD 6245.8 or median 586.0) for the Cochrane and 19 888.5 (SD 32 925.7 or median 6566.5) patients for the non-Cochrane reviews. The percentage of systematic reviews that achieved the OIS for all-cause mortality outcome were 0% Cochrane and 25% for non-Cochrane reviews; for semiobjective outcome 17% for Cochrane and 46% for non-Cochrane reviews and for subjective outcome 45% for Cochrane and 72% for non-Cochrane reviews.ConclusionsThe number of systematic reviews that meet an optimal information size is low and varies depending on the type of outcome and the type of publication. Less than half of primary outcomes synthesised in systematic reviews achieve the OIS, and therefore the conclusions are subject to substantial uncertainty.

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18 Years of Medication-Related Osteonecrosis of the Jaw (MRONJ) Research: Where Are We Now?—An Umbrella Review

Applied Sciences ◽

10.3390/app11198818 ◽

2021 ◽

Vol 11 (19) ◽

pp. 8818

Author(s):

Roberto Sacco ◽

Monica Diuana Calasans-Maia ◽

Julian Woolley ◽

Oladapo Akintola ◽

Carlos Fernando de Almeida Barros Mourão ◽

...

Keyword(s):

Systematic Reviews ◽

Case Reports ◽

Case Series ◽

Osteonecrosis Of The Jaw ◽

Umbrella Review ◽

Severe Condition ◽

Manual Search ◽

Number Of Patients ◽

Retrospective Cohort Studies ◽

Study Designs

Background: Osteonecrosis of the jaw (ONJ) is a condition affecting patients exposed to medications used to treat benign and malignant conditions of bone tissue. Many studies have highlighted that ONJ is a severe condition, which is very challenging to manage, especially in individuals with oncologic disease. The aim of this umbrella review is to analyze all available interventional and non-interventional systematic reviews published on medication-related osteonecrosis of the jaw (MRONJ) and summarize this evidence. Material and methods: A multi-database search (PubMed, MEDLINE, EMBASE and CINAHL) was performed to identify related multi-language papers published from January 2003 until June 2021. An additional manual search was also performed in systematic review registries (PROSPERO, INPLASY, JBI and OFS) to identify possible missing reviews. Data were extracted from relevant papers and analyzed according to the outcomes selected in this review. Results: The search generated 25 systematic reviews eligible for the analysis. The total number of patients included in the analysis was 80,840. Of the reviews, 64% (n = 16) were non-interventional and 36% (n = 9) were interventional. Study designs included case series 20.50% (n = 140), retrospective cohort studies 12.30% (n = 84) and case reports 12.20% (n = 83). It was unclear what study design was used for 277 studies included in the 25 systematic reviews. Conclusions: The data reviewed confirmed that the knowledge underpinning MRONJ in the last 20 years is still based on weak evidence. This umbrella review highlighted a widespread low-level quality of studies and many poorly designed reviews.

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Susceptibility to Fraud in Systematic Reviews

Anesthesiology ◽

10.1097/aln.0b013e3181c14c3d ◽

2009 ◽

Vol 111 (6) ◽

pp. 1279-1289 ◽

Cited By ~ 32

Author(s):

Emmanuel Marret ◽

Nadia Elia ◽

Jørgen B. Dahl ◽

Henry J. McQuay ◽

Steen Møiniche ◽

...

Keyword(s):

Systematic Reviews ◽

Surgical Patients ◽

Relevant Difference ◽

Number Of Patients ◽

Subgroup Analyses ◽

Current Article ◽

Web Of Knowledge ◽

Meta Analyses ◽

The Impact

Background Dr. Scott Reuben allegedly fabricated data. The authors of the current article examined the impact of Reuben reports on conclusions of systematic reviews. Methods The authors searched in ISI Web of Knowledge systematic reviews citing Reuben reports. Systematic reviews were grouped into one of three categories: I, only cited but did not include Reuben reports; II, retrieved and considered, but eventually excluded Reuben reports; III, included Reuben reports. For quantitative systematic reviews (i.e., meta-analyses), a relevant difference was defined as a significant result becoming nonsignificant (or vice versa) by excluding Reuben reports. For qualitative systematic reviews, each author decided independently whether noninclusion of Reuben reports would have changed conclusions. Results Twenty-five systematic reviews (5 category I, 6 category II, 14 category III) cited 27 Reuben reports (published 1994-2007). Most tested analgesics in surgical patients. One of 6 quantitative category III reviews would have reached different conclusions without Reuben reports. In all 6 (30 subgroup analyses involving Reuben reports), exclusion of Reuben reports never made any difference when the number of patients from Reuben reports was less than 30% of all patients included in the analysis. Of 8 qualitative category III reviews, all authors agreed that one would certainly have reached different conclusions without Reuben reports. For another 4, the authors' judgment was not unanimous. Conclusions Carefully performed systematic reviews proved robust against the impact of Reuben reports. Quantitative systematic reviews were vulnerable if the fraudulent data were more than 30% of the total. Qualitative systematic reviews seemed at greater risk than quantitative.

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FC13-03 - Stress, suicidal behaviour and genes

European Psychiatry ◽

10.1016/s0924-9338(11)73588-x ◽

2011 ◽

Vol 26 (S2) ◽

pp. 1884-1884

Author(s):

D. Wasserman ◽

Y. Ben-Efraim ◽

J. Wasserman ◽

M. Sokolowski

Keyword(s):

Hpa Axis ◽

Suicidal Behaviors ◽

Brain Functions ◽

Genes And Environment ◽

Hpa Axis Dysregulation ◽

Systemic Stress ◽

Suicide Behaviors ◽

Hpa Axis Activity ◽

Higher Brain Functions

According to a stress diathesis model, genes and environment, as well as possible interactions in-between (GxE), may result in vulnerability towards suicidal behaviors (SB), characterized by behavioral trigger endophenotypes such as increased depression-intensity and aggression/ anger/ impulsivity. Excessive stress has the potential to induce unfavorable effects in a variety of higher brain-functions, incurred as side effects to maladaptive responses in the genetically controlled stress-responsive neurosystems e.g. in the hypothalamic- pituitary-adrenal (HPA) axis. HPA-axis dysregulation is regarded as an endophenotype of depression-, anxiety- and alcohol abuse disorders, commonly found also in suicide behaviors. Various neurobiological alterations, suggesting abnormal HPA-axis activity and reactivity, have also been demonstrated to occur in suicidal behaviors incl. completed suicides. The HPA axis is a major systemic stress-modulator being mainly controlled by the regulatory corticotrophin releasing hormone receptor 1 (CRHR1) gene. An overview will be presented of the role of the HPA axis in suicidal behaviors with a focus on CRHR1 gene.

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Clinical characteristics and outcomes of hyponatraemia associated with oral water intake in adults: a systematic review

BMJ Open ◽

10.1136/bmjopen-2020-046539 ◽

2021 ◽

Vol 11 (12) ◽

pp. e046539

Author(s):

Gopala K Rangan ◽

Nilofar Dorani ◽

Miranda M Zhang ◽

Lara Abu-Zarour ◽

Ho Ching Lau ◽

...

Keyword(s):

Water Intake ◽

Systematic Reviews ◽

Clinical Characteristics ◽

Case Reports ◽

Daily Intake ◽

Population Based ◽

Fluid Restriction ◽

Excess Water ◽

Median Volume ◽

Meta Analyses

IntroductionExcessive water intake is rarely associated with life-threatening hyponatraemia. The aim of this study was to determine the clinical characteristics and outcomes of hyponatraemia associated with excess water intake.MethodsThis review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All studies (case reports, observational or interventional studies) reporting excess water intake and hyponatraemia in adults (1946–2019) were included.ResultsA total of 2970 articles were identified and 177 were included (88.7% case reports), consisting of 590 patients. The mean age was 46±16 years (95% CI 44 to 48 years), 47% female, 52% had a chronic psychiatric disorder and 31% had no underlying condition. The median volume of water consumed and serum sodium at presentation was 8 L/day (95% CI 8.9 to 12.2 L/day) and 118 mmol/L (95% CI 116 to 118 mmol/L), respectively. The motivator for increased water consumption was psychogenic polydipsia (55%); iatrogenic (13%); exercise (12%); habitual/dipsogenic polydipsia (7%) and other reasons (13%). The clinical features on presentation were severe in 53% (seizures, coma); moderate in 35% (confusion, vomiting, agitation) and mild in 5% (dizziness, lethargy, cognitive deficit) and not reported in 5% of studies. Treatment was supportive in 41% of studies (fluid restriction, treatment of the underlying cause, emergency care), and isotonic and hypertonic saline was used in 18% and 28% of cases, respectively. Treatment-related complications included osmotic demyelination (3%) and rhabdomyolysis (7%), and death occurred in 13% of cases.ConclusionWater intoxication is associated with significant morbidity and mortality and requires daily intake to substantially exceed population-based recommendations. The limitations of this analysis are the low quality and high risk of bias of the included studies.PROSPERO registration numberA pre-existing protocol in the international prospective register of systematic reviews was updated to incorporate any new amendments and reregistered at http://www.crd.york.ac.uk/PROSPERO (registration no. CRD42019129809).

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Abstract TP63: Risk of Contrast Induced Nephropathy After Emergency CTA in Stroke Patients: A Meta-Analysis

Stroke ◽

10.1161/str.51.suppl_1.tp63 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Thirumalaivasan Dhasakeerthi ◽

Muhammad Ishfaq ◽

Balaji Krishnaiah ◽

Andrei Alexandrov ◽

Georgios Tsivgoulis

Keyword(s):

Contrast Agents ◽

Systematic Reviews ◽

Meta Analysis ◽

Significant Heterogeneity ◽

Case Control Studies ◽

Contrast Induced Nephropathy ◽

Number Of Patients ◽

Increased Risk ◽

Meta Analyses ◽

Contrast Ct

Background: Contrast agents for computed tomographic angiography (CTA) and perfusion (CTP) are presumed to be nephrotoxic prompting many hospitals to require serum creatinine values prior to imaging likely causing delays in door to needle times. The objective of this study is to assess the risk of developing contrast induced acute kidney injury (AKI) in patients who are undergoing CTA and CTP. Materials and Methods: We have searched the electronic databases up to July 2019 for studies that reported incidence of AKI in patients who have undergone CTA and CTP. We calculated pooled odds ratios and 95% CIs by using random-effects models for the primary end point being AKI due to contrast induced nephropathy. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines for systematic reviews and meta-analyses. Results: Eight case control studies assessing 4,449 patients have been included in the study. The odds of AKI in CTA/CTP patients versus non-contrast CT was not statistically significant (odds ratio = 0.53, 95% CI = 0.20-1.39, p=0.199). There was no significant heterogeneity between the studies (Cochran’s Q statistic 3.632, df 4; P = .461, I2=2.514%). Overall, no AKI patient required hemodialysis due to contrast induced nephropathy. The absolute number of patients who developed AKI among CTA/CTP patients was lower than among patients who underwent just non-contrast CT (67 versus 87, NS). Conclusion: The use of contrast agents for CTA/CTP in acute stroke is not associated with an increased risk of developing contrast induced nephropathy nor AKI requiring dialysis.

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