Association between FIASMA psychotropic medications and reduced risk of intubation or death in individuals with psychiatric disorders hospitalized for severe COVID-19: an observational multicenter study
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Abstract
The acid sphingomyelinase (ASM)/ceramide system may provide a useful framework for better understanding SARS-CoV-2 infection and the repurposing of psychotropic medications functionally inhibiting the acid sphingomyelinase/ceramide system (named FIASMA psychotropic medications) against COVID-19. We examined the potential usefulness of FIASMA psychotropic medications in patients with psychiatric disorders hospitalized for severe COVID-19, in an observational multicenter study conducted at Greater Paris University hospitals. Of 545 adult inpatients, 164 (30.1%) received a FIASMA psychotropic medication upon hospital admission for COVID-19. We compared the composite endpoint of intubation or death between patients who received a psychotropic FIASMA medication at baseline and those who did not in time-to-event analyses adjusted for sociodemographic characteristics, psychiatric and other medical comorbidity, and other medications. FIASMA psychotropic medication use at baseline was significantly associated with reduced risk of intubation or death in both crude (HR = 0.42; 95%CI = 0.31–0.57; p < 0.01) and primary inverse probability weighting (IPW) (HR = 0.50; 95%CI = 0.37–0.67; p < 0.01) analyses. This association was not specific to one FIASMA psychotropic class or medication. Patients taking a FIASMA antidepressant at baseline had a significantly reduced risk of intubation or death compared with those taking a non-FIASMA antidepressant at baseline in both crude (HR = 0.57; 95%CI = 0.38–0.86; p < 0.01) and primary IPW (HR = 0.57; 95%CI = 0.37–0.87; p < 0.01) analyses. These associations remained significant in multiple sensitivity analyses. Our results show the potential importance of the ASM/ceramide system framework in COVID-19 and support the continuation of FIASMA psychotropic medications in these patients and the need of large- scale clinical trials evaluating FIASMA medications, and particularly FIASMA antidepressants, against COVID-19.
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SciScore for 10.1101/2021.02.18.21251997: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: This observational study using routinely collected data received approval from the Institutional Review Board of the AP-HP clinical data warehouse (decision CSE-20-20_COVID19, IRB00011591).
Consent: AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved studies through a transparency portal in accordance with European Regulation on data protection and authorization n°1980120 from National Commission for Information Technology and Civil Liberties (CNIL).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
… SciScore for 10.1101/2021.02.18.21251997: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: This observational study using routinely collected data received approval from the Institutional Review Board of the AP-HP clinical data warehouse (decision CSE-20-20_COVID19, IRB00011591).
Consent: AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved studies through a transparency portal in accordance with European Regulation on data protection and authorization n°1980120 from National Commission for Information Technology and Civil Liberties (CNIL).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources All analyses were conducted in R software version 2.4.3 (R Project for Statistical Computing). R Project for Statisticalsuggested: (R Project for Statistical Computing, RRID:SCR_001905)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has several limitations. First, there are two possible major inherent biases in observational studies: unmeasured confounding and confounding by indication. We tried to minimize the effects of confounding in several different ways. First, we used an analysis with inverse probability weighting to minimize the effects of confounding by indication [23, 24]. Second, we performed multiple sensitivity analyses, which showed similar results. Finally, although some amount of unmeasured confounding may remain, our analyses adjusted for numerous potential confounders. Other limitations include missing data for some baseline characteristic variables (i.e., 11.5%), which might be explained by the overwhelming of all hospital units during the COVID-19 peak incidence, and different results might have been observed during a lower COVID-19 incidence period. However, imputation of missing data did not alter the significance of our results (data available on request). Second, inflation of type I error might have occurred in secondary exploratory analyses due to multiple testing. Third, data on several FIASMA psychotropic medications, such as fluvoxamine or maprotiline, were not available because no patients with mental disorder hospitalized for severe COVID-19 received them at study baseline in AP-HP hospitals. Fourth, this study cannot establish a causal relationship between FIASMA psychotropic medication use and reduced risk of intubation or death [42]. Finally, despite the multice...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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SciScore for 10.1101/2021.02.22.21252209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Severe COVID-19 was defined as having at least one of the following criteria at hospital admission : respiratory rate > 24 breaths/min or < 12 breaths/min, resting peripheral capillary oxygen saturation in ambient air < 90%, temperature > 40°C, systolic blood pressure < 100 mm Hg, or high lactate levels>2mmol/L.20–22 This observational study using routinely collected data received approval from the Institutional Review Board of the AP-HP clinical data warehouse (decision CSE-20-20_COVID19, IRB00011591, April 8th, 2020).
Consent: AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved …SciScore for 10.1101/2021.02.22.21252209: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Severe COVID-19 was defined as having at least one of the following criteria at hospital admission : respiratory rate > 24 breaths/min or < 12 breaths/min, resting peripheral capillary oxygen saturation in ambient air < 90%, temperature > 40°C, systolic blood pressure < 100 mm Hg, or high lactate levels>2mmol/L.20–22 This observational study using routinely collected data received approval from the Institutional Review Board of the AP-HP clinical data warehouse (decision CSE-20-20_COVID19, IRB00011591, April 8th, 2020).
Consent: AP-HP clinical Data Warehouse initiatives ensure patient information and informed consent regarding the different approved studies through a transparency portal in accordance with European Regulation on data protection and authorization n°1980120 from National Commission for Information Technology and Civil Liberties (CNIL).Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Medications with functional inhibition effect on acid sphingomyelinase (ASM): FIASMA medications were defined as having a substantial in vitro functional inhibition effect on ASM (i.e., a residual ASM activity lower than 50%), as detailed elsewhere,5–9 and were divided into the following classes according to their Anatomical Therapeutic Chemical (ATC) code:25 FIASMA alimentary tract and metabolism medications (e.g., loperamide); cardiovascular system medications, subdivided into calcium channel blockers (e.g., amlodipine) and other cardiovascular medications (e.g., carvedilol); nervous system medications, subdivided according to ATC codes into psychoanaleptic (e.g., amitriptyline) and psycholeptic medications (e.g., chlorpromazine); and respiratory system medications (e.g., desloratadine). ATCsuggested: None3 (R Project for Statistical Computing). R Project for Statisticalsuggested: (R Project for Statistical Computing, RRID:SCR_001905)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has several limitations. First, there are two possible major inherent biases in observational studies: unmeasured confounding and confounding by indication. However, in the case of FIASMA medications, including several antidepressants and cardiovascular system medications, confounding by indication may typically result in increased adverse medical outcomes associated with these medications,49 not better outcomes as suggested by our findings. We tried to minimize the effects of confounding in several different ways. First, we used an analysis with inverse probability weighting to minimize the effects of confounding by indication,27,28 resulting in non-substantial between-group differences in clinical characteristics (all SMD<0.1) in both the IPW primary analysis and the Cox regression analysis in the matched analytic sample. Second, we performed multiple sensitivity analyses, which showed similar results. Finally, although some amount of unmeasured confounding may remain, our analyses adjusted for numerous potential confounders. Other limitations include missing data for some baseline characteristic variables (i.e., 11.5%), which might be explained by the overwhelming of all hospital units during the COVID-19 peak incidence, and different results might have been observed during a lower COVID-19 incidence period. However, imputation of missing data did not alter the significance of our results (data available on request). Second, inflation of type I error might have o...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- No funding statement was detected.
- No protocol registration statement was detected.
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