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Compared to before the pandemic, there has been an increase in psychotropic drug use and psychiatric disorders in Danish children, adolescents and young adults. This is shown by a large Danish study including all year-old in Denmark with data until June In addition, there has been an increase in youths assigned with a clinical psychiatric disorder diagnosis of ADHD or, to a lesser extent, anxiety disorders. Our study indicates that more children and young people experienced severe mental problems that required treatment with psychotropic medication during and after the pandemic than before. In the study, which was just released in JAMA Psychiatry , the authors modelled the pre-pandemic monthly rate of filled prescriptions for psychotropic medication and registered psychiatric disorder diagnoses. Using this model, they showed a surplus of observed use of medicines and rates of diagnoses compared to the expected numbers during the pandemic. The researchers behind the study emphasise that the findings do not point to the explanations of what specifically caused the increase in psychopathology. Professor Christoph U. Danish children, adolescents and young adults are using more psychotropic drugs after the COVID pandemic. Share quote. She clarifies: - The increase in psychopathology occurred in both children and adolescents with and without a psychiatric history. Concerning results Professor Christoph U. Show more About the study. From January through June , there were Due to the tax-free health care system and a unique personal identification number assigned to all individuals living in Denmark, the study used individual-level data from nationwide registers holding information on filled psychotropic prescription medication and inpatient and outpatient hospital psychiatric disorder diagnosis. Meet the researcher. Back to Press and News Room. Share on. Editing was completed:

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A, Life support was defined as invasive mechanical ventilation, circulatory support, or kidney replacement therapy. There were missing data in 11 patients for the primary outcome. Red represents the worse outcomes and blue represents better outcomes. B, There were 14 patients who were not followed up for the full 90 days 7 patients in each intervention group and who were included until the last day they were known to be alive. The median follow-up time was 90 days IQR, days in the 12 mg of dexamethasone group and 90 days IQR, days in the 6 mg of dexamethasone group. The time to death was compared post hoc using unadjusted Cox regression. The median differences for the outcomes of days alive without life support and days out of the hospital and the analyses of the single components of the composite outcomes appear in eTable 8 in Supplement 2. In a randomized trial conducted in of patients with COVID and severe hypoxemia, 12 mg of dexamethasone did not statistically significantly reduce the number of days patients were alive without life support at 28 days compared with 6 mg of dexamethasone. Click the related article link for full trial details Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID and severe hypoxemia? This difference was not statistically significant. Meaning Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly increase the number of days alive without life support at 28 days. Importance A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID, but a higher dose may benefit those with more severe disease. End of day follow-up was on August 19, Main Outcomes and Measures The primary outcome was the number of days alive without life support invasive mechanical ventilation, circulatory support, or kidney replacement therapy at 28 days and was adjusted for stratification variables. The median number of days alive without life support was Mortality at 28 days was Mortality at 90 days was Serious adverse reactions, including septic shock and invasive fungal infections, occurred in However, the trial may have been underpowered to identify a significant difference. Trial Registration ClinicalTrials. Patients with critical COVID are characterized by severe pulmonary inflammation and hypoxemia, which often leads to use of high-flow oxygen, mechanical ventilation and, in case of further disease progression, circulatory support and kidney replacement therapy. Dexamethasone is recommended by the World Health Organization 2 for patients with severe and critical COVID based on a prospective meta-analysis 3 of 7 randomized trials reporting reduced short-term mortality with the use of systemic glucocorticoids. Among the remaining 6 trials in the meta-analysis, 3 most evaluated daily doses of glucocorticoids that were higher than 6 mg of dexamethasone median dose in dexamethasone equivalents, 12 mg \[range, mg\]. However, there are concerns about adverse reactions with the use of higher doses of glucocorticoids, 11 particularly reports of severe fungal infections, such as mucormycosis, in patients with COVID treated with glucocorticoids. The hypothesis was that a higher daily dose of dexamethasone 12 mg compared with the currently recommended daily dose 6 mg would increase the number of days alive without life support at 28 days in these patients. This trial was an investigator-initiated, international, parallel-group, stratified, blinded randomized clinical trial. The trial protocol was approved by the Danish Medicines Agency, the ethics committee of the Capital Region of Denmark, and institutionally at each trial site. Before enrollment was completed, the trial protocol and statistical analysis plan were published 14 and also appear in Supplement 1. A data and safety monitoring committee oversaw the safety of the trial participants and conducted 1 planned interim analysis. Informed consent was obtained from the patients or their legal surrogates according to national regulations. At many institutions, enrollment was allowed as an emergency procedure ie, assent was provided by a physician who was not involved in the trial and consent was later obtained from the patient or a relative to continue participation. If consent was withdrawn or not granted, permission was sought from the patient or a relative to continue the collection and use of data. Patients underwent screening and randomization between August 27, , and May 20, , at 26 hospitals 11 in Denmark, 12 in India, 2 in Sweden, and 1 in Switzerland. At 2 of the Danish hospitals, there were multiple sites at intensive care units and departments of infectious diseases and pulmonary medicine so the total number of trial sites was We excluded patients who 1 were treated with systemic glucocorticoids in doses higher than 6 mg of dexamethasone equivalents for indications other than COVID or had been treated with systemic glucocorticoids for COVID for 5 days or longer, 2 had invasive fungal infection or active tuberculosis, 3 had known hypersensitivity to dexamethasone, and 4 were pregnant. The full details regarding the inclusion and exclusion criteria appear in the eMethods in Supplement 2. Randomization was performed using a centralized, computer-generated allocation sequence stratified by trial site, by age of younger than 70 years, and by whether the patient required invasive mechanical ventilation at the time of screening. Treatment assignments were concealed from patients, clinicians, investigators, trial statisticians, the data and safety monitoring committee, and the management committee when it wrote the first version of the abstract eMethods in Supplement 2. A daily dose with 12 mg of dexamethasone as The use of betamethasone was allowed at sites where dexamethasone was not available 1 hospital in Sweden because the drugs are diastereomers and are likely equipotent. A team of unblinded trial staff, who were not involved in the care of trial patients or in the entry of outcome data or the statistical analysis, prepared the masked trial medication from the medication available at local hospital pharmacies the brand names appear in eFigure 1 in Supplement 2. The staff was instructed not to reveal the treatment allocation unless the participant was subject to emergency unblinding occurred in 1 patient who was randomized to 6 mg of dexamethasone. If the patient had been treated with dexamethasone for COVID prior to enrollment, the intervention period was shortened so that no patients received dexamethasone for more than 10 days per the trial protocol. All other interventions were at the discretion of the clinicians; however, we recommended against the use of other immunosuppressive agents for COVID The trial investigators or staff reported any serious adverse events to the coordinating centers and entered the baseline characteristics, process variables, and outcome data from the patient files into web-based case report forms for days 1 to 14, day follow-up, and day follow-up. When available, regional and national registries were used for follow-up and patients or their surrogates were contacted directly if additional data were needed. Trial data were monitored at the sites including consent and source data verification by independent monitors according to a prespecified monitoring plan and centrally by staff from the coordinating centers. The primary outcome was the number of days alive without life support invasive mechanical ventilation, circulatory support, or kidney replacement therapy at 28 days after randomization. All outcome definitions appear in the eMethods in Supplement 2. The secondary outcomes were the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and the number of patients with 1 or more serious adverse reactions at 28 days ie, new episodes of septic shock, invasive fungal infection, clinically important gastrointestinal bleeding, or anaphylactic reaction to dexamethasone. Three additional secondary outcomes, including health-related quality of life measured using the 5-dimension, 5-level European Quality of Life questionnaire and the European Quality of Life visual analog scale, will be assessed at days after randomization Supplement 1. The statistician on the data and safety monitoring committee conducted the interim analysis after the first patients had been followed up for 28 days. For the secondary mortality outcomes, a hierarchical testing procedure was specified. The statistical analyses were performed according to the statistical analysis plan with some modifications a 2-step procedure was used to analyze all binary outcomes due to convergence problems and post hoc sensitivity analyses were added; the details appear in Supplement 1. In the per-protocol population, patients with 1 or more major protocol violations were excluded eMethods in Supplement 2. In the primary outcome analysis, the number of days alive without life support within the day period was analyzed using the Kryger Jensen and Lange test 19 and was adjusted for stratification variables. The Kryger Jensen and Lange test increases power when used for data sets with zero values ie, many patients who were expected to have 0 days alive without life support. The secondary analysis of the primary outcome was adjusted for the stratification variables and additional predefined risk factors at baseline history of ischemic heart disease or heart failure, diabetes, chronic obstructive pulmonary disease, use of immunosuppressive therapy within prior 3 months, use of circulatory support, and use of kidney replacement therapy and was performed in the per-protocol population and in prespecified subgroups including test of interaction using the Wald test. The protocol was changed on January 9, , to include the subgroup analyses by enrollment geographic region and by use of IL-6 receptor antagonists and to exclude septic shock to reduce the overall number of subgroup analyses. For the secondary outcomes, the Kryger Jensen and Lange test 19 was used and the logistic regression adjusted for the stratification variables and g-computation or for the generalized linear models with log links and binomial error distributions. Unadjusted Fisher exact testing also was performed. Logical imputations were made for missing primary outcome data for 2 patients. One patient was declared by a physician on day 25 as being well enough to board an airplane; however, this patient was lost to follow-up and assumed to be alive without life support from days 25 to The relatives of another patient who died on day 46 reported that the patient had been treated with kidney replacement therapy after hospital discharge, therefore, this patient was assumed to have been receiving kidney replacement therapy from hospital discharge to day 28 eMethods in Supplement 2. Best-worst and worst-best imputations were made for 11 patients who withdrew consent during the day data collection period without data on the use of life support or vital status from the date of withdrawal. These 11 patients were included in the analysis of serious adverse reactions without imputation of missing data. An additional 2 patients withdrew consent before 90 days 1 was lost to follow-up and 1 had missing life support data at day The day outcomes were analyzed without any imputation. These analyses were performed using R versions 3. In another post hoc analysis decided before database lock, we analyzed the primary outcome by assigning dead participants the worst possible outcome ie, 0 days alive without life support as was done in previous trials. An additional post hoc analysis for time to death compared the 2 groups using unadjusted Cox regression. Another 8 patients were erroneously randomized and were included in the analyses eTables 1A-1B and eFigures in Supplement 2. Data for the primary outcome were obtained for patients in the mg group and in the 6-mg group. Patient characteristics at baseline were largely similar in the 2 groups; however, the prevalence of coexisting diabetes differed Table 1. The end of day follow-up was on August 19, Both groups had received dexamethasone for a median of 1 day before enrollment. The use of respiratory, circulatory, and kidney support and the use of other anti-inflammatory, antiviral, and antibacterial agents was similar between groups at baseline Table 1. The assigned trial intervention was received per protocol by of patients The duration of the intervention was similar in the 2 groups median, 7 days \[IQR, 5. During the intervention period, 10 of patients 2. Nine 1. At 28 days after randomization, the median number of days alive without life support was The results were similar in the preplanned Table 2 and eTables in Supplement 2 and in the post hoc sensitivity analyses Table 2 ; eFigure 4 and eTables in Supplement 2. In the predefined subgroup analysis, no statistically significant heterogeneity was found for the effect of the trial intervention on the primary outcome Figure 3. The single components of the composite primary outcome were similar between groups Table 2 and eTable 8 in Supplement 2. The percentages of patients with 28 days alive without life support were At 90 days, the median number of days alive without life support was At 90 days, the median number of days alive and out of the hospital was At 28 days, a total of of patients At 90 days, of patients At 28 days, 56 of patients in the 12 mg of dexamethasone group The components of the composite adverse reaction outcome appear in Table 2 and eTable 8 in Supplement 2 ; none had an anaphylactic reaction to dexamethasone. The total number of patients with 1 or more serious adverse reactions or serious adverse events was Extracorporeal membrane oxygenation was used in 3 patients 0. None of the analyzed secondary outcomes were statistically significant and the subgroup analyses did not support heterogeneity for the intervention effect. The number of patients with serious adverse reactions ie, septic shock, invasive fungal infection, and clinically important gastrointestinal bleeding appeared similar between the groups. Other trials have assessed treatments providing anti-inflammatory effects in addition to that of 6 mg of dexamethasone in patients with COVID These differences may be due to differences in anti-inflammatory modulation, patient populations, outcome definitions, statistical frameworks REMAP-CAP used bayesian statistics , or sample sizes and event rates. Additional analyses of the current trial outcomes at days and a bayesian analysis of outcomes at 28 days and at 90 days , 14 , 22 and a planned prospective meta-analysis of the trials assessing high-dose vs standard-dose dexamethasone in patients with COVID and hypoxemia 23 may provide additional insights. The strengths of this trial include the pragmatic protocol, its relatively large sample size, inclusion of most of the eligible patients, allocation concealment and blinding, the high percentage of follow-up at 28 days, and the variety of hospitals and countries involved. Septic shock and invasive fungal infections were prespecified secondary safety outcomes and therefore accurately captured. The results were consistent in multiple sensitivity analyses, as well as in analyses of the per-protocol population and in the prespecified subgroups. Together, these characteristics increase the internal and external validity of our results. This trial had several limitations. First, the null result may reflect limited power to detect statistically significant differences for the primary outcome as well other outcomes and in the subgroup analyses. Second, some baseline variables such as ethnicity were not collected, and some characteristics such as prevalence of diabetes differed between the groups. However, a predefined secondary analysis adjusting for diabetes and other important risk factors supported the primary result. Third, the intervention period was only 6 days in some patients per protocol because the trial design allowed up to 4 days of dexamethasone use before enrollment, which may have reduced any effect of the intervention. Fourth, the distribution of the primary and secondary outcome data was not normal. To mitigate this, a newly developed statistical test that accounts for data sets with many zero values was used, and post hoc bootstrapping was used to test the results further. Sixth, changes in the treatment of COVID during the trial such as increased use of IL-6 receptor antagonists may have influenced the results. Published Online: October 21, Munch, MD; Sheila N. Divatia, MD; Anne C. Wamberg, MD; Mehul S. Shah, MD; Iben S. Darfelt, MD; Vibeke L. Meyhoff, MD; Gitte K. Jensen; Jens W. Leistner, BSc; Trine B. Jonassen, BSc; Camilla M. Kristensen, BSc; Esben C. Clapp, BSc; Carl J. Jensen, MD; Liv S. Halstad, BSc; Emilie R. Hatley; Tobias S. Jha, V. Author Contributions: Drs Munch and Lange had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Hammond, John, V. Jha, and Venkatesh led the set up and conduct of the trial in India. Jensen, V. Jha, Venkatesh, Perner. Jha, Venkatesh. Jha, Cronhjort, Gluud, Hedman, M. Jha, Cronhjort, Gluud, V. Dr Divatia reported receiving personal fees from Edwards Lifesciences. Mr Leistner reported receiving grants from the Novo Nordisk Foundation. Jensen reported receiving grants from the Novo Nordisk Foundation and receiving nonfinancial support from the Research Council at Rigshospitalet. Data Sharing Statement: See Supplement 4. Additional Contributions: We thank the patients and relatives for agreeing to participate in the COVID STEROID 2 trial, the clinical and research staff at the participating hospitals, the regulatory authorities in the participating countries for the expedited handling of the protocol, and the funding sources. Download PDF Comment. Visual Abstract. View Large Download. Figure 1. Figure 2. Figure 3. Table 1. Baseline Characteristics of the Patients a. Table 2. Primary and Secondary Outcomes. Supplement 1. Trial protocol and statistical analysis plan. Supplement 2. Masking of Trial Medication eFigure 2. Number of Enrolments per Site eFigure 3. Number of Enrolments per Month eFigure 4. Supplement 3. Nonauthor collaborators. Supplement 4. Data sharing statement. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID a meta-analysis. Dexamethasone in hospitalized patients with Covid Effect of hydrocortisone on day mortality or respiratory support among critically ill patients with COVID a randomized clinical trial. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID the CoDEX randomized clinical trial. Published online June 17, Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study. Clinical pharmacology of corticosteroids. Interleukin-6 receptor antagonists in critically ill patients with Covid Mortality in multicenter critical care trials: an analysis of interventions with a significant effect. A multiple testing procedure for clinical trials. A novel high-power test for continuous outcomes truncated by death. Google Scholar. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Higher vs standard doses of dexamethasone in patients with COVID and hypoxia: a prospective meta-analysis. Published May 31, Accessed October 8, William M. Alpern, MD; Patricia F. This open label clinical trial compares the effects of dexamethasone vs usual care on the number of days alive and free of mechanical ventilation at day 28 among COVID patients in Brazil with moderate to severe acute respiratory distress syndrome ARDS. Bruno M. Tomazini, MD; Israel S. Silva; Franca P. Baldassare; Eduardo L. Moura, MD; Michele O. Honorato, MD; Andre N. Amendola, MD; Roberta M. Roepke, MD; Daniela H. Freitas, MD; Daniel N. Fernandes, MD; Livia M. Melro, MD; Gedealvares F. Steven A. Higgins, PhD; Colin J. Marie W. Save Preferences. Privacy Policy Terms of Use. View Correction. This Issue. Views , Citations View Metrics. X Facebook More LinkedIn. Original Investigation. Article Information. Key Points Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID and severe hypoxemia? Trial Design and Oversight. Trial Sites and Patients. Data Collection and Monitoring. Sample Size Calculation. Statistical Analysis. Trial and Concomitant Interventions. Primary Outcome. Secondary Outcomes. Serious Adverse Reactions and Events. Back to top Article Information. Access your subscriptions. Access through your institution. Add or change institution. Free access to newly published articles. Purchase access. Rent article Rent this article from DeepDyve. Sign in to access free PDF. Save your search. Customize your interests. Create a personal account or sign in to:. Privacy Policy. Make a comment.

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