key: cord-0910575-wfa52w27 authors: Plasencia-Garcia, B. O.; Rodriguez-Menendez, G.; Rico-Rangel, M. I.; Rubio-Garcia, A.; Torello-Iserte, J.; Crespo-Facorro, B. title: Drug-Drug interactions between COVID-19 treatments and antipsychotics drugs: integrated evidence from 4 databases and a systematic review date: 2020-06-08 journal: nan DOI: 10.1101/2020.06.04.20122416 sha: 1e54ba22a74ada036deb8f071b38d8a6fb02c94d doc_id: 910575 cord_uid: wfa52w27 Relevance: Management of symptoms like anxiety, delirium and agitation cannot be neglected in COVID-19 patients. Antipsychotics are usually used for the pharmacological management of delirium, and confusion and behavioral disturbances. The selection of concomitant COVID-19 medications and antipsychotics should be evidence-based and closely monitored Objective: To systematically review evidence-based available on drug-drug interactions between COVID-19 treatments and antipsychotics. Evidence Review: Three databases were consulted: (a) Lexicomp Drug Interactions, (b) Micromedex Solutions Drugs Interactions, (c) Liverpool Drug Interaction Group for COVID-19 therapies. To acquire more information on QT prolongation and TdP, the CredibleMeds QTDrugs List was searched. Based on the information collected, the authors made a recommendation agreed to by consensus. In addition, a systematic review was conducted to find the clinical outcomes of drug-drug interactions between COVID-19 treatments and antipsychotics Results: The main interaction between COVID-19 drugs and antipsychotics are the risk of QT prolongation and TdP, and CYP interactions. Remdesivir, favipiravir, baricinitib, and anakinra can be used concomitantly with antipsychotics with no risk of drug-drug interaction (except for hematological risk with clozapine and baricinitib). Tocilizumab is rather safe to use in combination with antipsychotics, although it can restore the activity of CYP3A4 and therefore its substrate metabolism may increase. The most demanding COVID-19 treatments for co-administration with antipsychotics are chloroquine, hydroxychloroquine, azithromycin (all prolong QT interval) and lopinavir / ritonavir (CYP interaction and risk of QT prolongation). Conclusions: We urge to development of evidence-based guidelines that can help clinicians decide the safest treatment combination and monitoring necessary for each particular patient. The selection of concomitant COVID-19 medications and antipsychotics should be evidence-based and closely monitored. The number of people affected by coronavirus disease 2019 worldwide is over 4.5M and rapidly increasing, and the importance of knowledge of symptom management and treatment for general practitioners and other clinicians must be stressed. Although the key symptoms are cough, fever, and breathlessness, anxiety, delirium, and agitation are also present in a large number of patients 1 . Up to 20-30% of COVID-19 patients will have with or develop delirium or changes in the mental health during their hospitalizations, and these numbers are as high as 60-70% in severely ill patients 2,3 . The duration of delirium has consistently proven an independent predictor of longer hospitalization, higher mortality, and higher cost [4] [5] [6] , and delirium is often inadequately managed 7 . Antipsychotics drugs (APs) are usually selected for the pharmacological management of delirium 8 , and confusion and behavioural disturbances associated with hospitalization of elderly patients 9,10 . COVID-19 patients are being treated with Chloroquine, Hydroxychloroquine 11,12 , Azithromycin, 13 and Lopinavir/ritonavir 14 , for the main symptoms, with risk of QT prolongation and TdP, and others drug-drug interactions (DDIs) in coadministration with antipsychotics. The very ill patients being treated, are the most likely to suffer from QT prolongation, because of the clinical condition known to prolong QT, and the concomitant drugs, and clinicians need to mitigate that risk 15 . This use is complicated by age-related decline in drug metabolism 16 , high incidence of concomitant physical illnesses, drug-drug interactions, and heightened sensitivity to APs [17] [18] [19] . In addition, APs are associated with a proarrhythmic state and an increased risk of sudden cardiac death (SCD), with no substantial differences between first and second generation antipsychotics, and a doseresponse effect 20, 21 . Antipsychotics (exception Aripiprazole and Lurasidone) seem to be associated with a prolonged QT interval and an increased risk of SCD 22 . There are differences among APs in the degree of cardiotoxic effects 23 . SCD describes the unexpected natural death from a cardiac cause, within a short a time of a person who often has no prior cardiological condition that would appear fatal 24 . Many antipsychotics show a certain degree of blockade of potassium channels coded by the human ether-à-go-go related gene (hERG), thus inducing a QT interval prolongation and increasing the risk of polymorphic ventricular tachycardia/ torsade de Pointes (TdP) 25,26 . The most common acquired cause of long QT syndrome and TdP is drug induced QT interval prolongation. Intensive Care Unit patients are particularly prone to experience a QTc interval prolongation mainly due to certain drugs that can prolong the repolarization phase, either by All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint their action mechanism or through the interaction with other drugs 27 . Elderly patients are in particularly prone to proarrhythmic risk with antipsychotics 28 . Also, the potential for pharmacokinetic DDIs of APs are mostly mediated by cytochrome P450 (CYP) enzymes metabolism, therefore physicians should be aware of coadministered drugs that may inhibit or induce these CYP enzymes 29-31 . The aim of our review is to analyze the risks of DDIs and cardiovascular adverse events of antipsychotics with the main treatments currently used for COVID-19. More so, SARS-CoV-2 primarily affects the elderly with other associated cardiovascular risk factors, which often require hospitalization, and treatment of which is esencial to knowing the risk and safety of antipsychotics associated with COVID-19 treatments. Drugs currently used in the treatment of SARS-CoV-2 32 , chloroquine, hydroxychloroquine, lopinavir/ritonavir, remdesivir, and tocilizumab have been reviewed. Also azithromycin with promising results 13 , and potential agents therapeutic agents such as favipiravir 33 , baricitinib 34 , and anakinra 35 . type of interaction, risk rating, and severity (both, according to the stratification in each database) and patient management recommendations. To find out more about QT prolongation and TdP, the CredibleMeds® QTDrugs List 41 was searched. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint After the above information had been collected, the authors made consensus recommendations based on the following: 1. Not recommended (red zone), if (1) coadministration contraindicated in one or more databases, or (2) both drugs classified as "Known Risk of TdP" (risk of QT prolongation or TdP). 2. Recommended with caution. Two categories: a) Potential interaction, which may require a dose adjustment, close monitoring, or choosing alternative agents, in two or more databases (orange zone). b) Potential interaction intensity likely to be weak. Additional action/monitoring or dose adjustment unlikely to be required, in two or more databases (yellow zone). 3. Recommended (green zone), if little or no evidence of clinically significant interaction is expected in two or more databases. When there were differences between databases, and it was not possible to reach an agreement by consensus, our recommendations reflect the most conservative approach. When QT-prolongation is the main risk, we present the APs in two groups according to CredibleMeds® ("Possible" or "Conditional" risk) to increase the clinical information. Additionally, a systematic review was conducted according to PRISMA guidelines 42 (registration number in PROSPERO CRD42020183202) to find clinical outcomes of drug-drug interactions between COVID-19 treatment and antipsychotics. We researched the following databases: MEDLINE, EMBASE, and Web of Science. The search was restricted to the English language using database filters. No dates restriction were imposed for the updated search. The search strategy will follow syntax: antipsychotic* AND (chloroquine OR hydroxychloroquine OR lopinavir OR ritonavir OR remdesivir OR tocilizumab OR azithromycin OR favipiravir OR baricitinib OR anakinra). The reference list of all identified articles identified were examined for any additional studies nor found in the first search. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint Inclusion and exclusion criteria: The characteristics for a study to be eligible were (1) Publication reporting clinically significant drug-drug interactions (between antipsychotics and COVID-10 treatment in adult patients (whatever the disease prescribed for), (2) Type of publication: randomized controlled trial, other controlled study, observational study, case report and case series. Exclusion criteria: (1) Only pharmacokinetic studies (no clinical outcome), (2) Unpublished studies or gray literature and conference articles. Three reviewers (G.R., A.R., M.R.) independently screened titles for the research question and criteria. When articles were deemed to meet the inclusion criteria by either reviewer, the abstract was analyzed. Full texts were retrieved when the reviewers were in agreement that the article met the inclusion criteria. Disagreements were solved by a fourth independent reviewer (B.P.). Rayyan QCR was used for duplicated data and screening 43 . Data extraction: Two authors reached an agreement regarding the type of data to be collected, and relevant information such as the study design, context of drug interactions, clinical outcome, other comedication data and the numbers and types of patients was recorded. Risk of bias and generalizability concerns in comparative studies were evaluated with an adaptation of the Newcastle-Ottawa quality assessment scale for case control and cohort studies 44 , an eight-item tool designed to rate methodological aspects of case-control and cohort studies, which includes three domains: study selection, comparability of cohorts on the basis of the design or analysis, and exposure. The overall score ranges from 0 to 9. Risk of bias and generalizability concerns in case reports and case series were evaluated with the Drug Interaction Probability Scale (DIPS) tool to assess the quality of papers retained 45 , This 10question tool evaluates drug interaction causation. Scores <2 indicate doubtful drug interaction, scores 2-4 possible, 5-8 probable and scores ≥ 9 indicate highly probable drug interaction. The authors' consensus recommendations are summarized in Table 1 . The primary interaction is the risk of QT prolongation and TdP because the three drugs for COVID-19, have "Known Risk of TdP" according to CredibleMeds®. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint Recommended use of APs with these treatments is summarized in Table 2 . Azithromycin is not included in the LiverpoolÓ Drug Interaction Group, and therefore, some APs are marked as authors' consensus agreement not possible. In that case, the recommendations reflect the most conservative approach, and they must be used with caution. The summary information about the risk rating, severity and patient management for each database is available in Supplement Tables 1-3. The recommended concomitant APs for use with these 3 COVID-19 drugs are: cariprazine, brexpiprazole and lurasidone. Asenapine may be used in combination with chloroquine and hydroxychloroquine, and olanzapine with hydroxychloroquine. This coadministration involves CYP interactions and the risk of QT prolongation and TdP. Lopinavir/ritonavir have "Possible Risk of TdP" according to CredibleMeds®. Lopinavir is metabolized primarily by hepatic CYP3A4 isoenzymes, and ritonavir is known to inhibit CYP3A4, CYP2D6, and to a lesser extent CYP2C9/10 and CYP2C19. Lopinavir/ritonavir is a strong inhibitor of CYP3A4, less of CYP2D6 and P-Glycoprotein (P-gp), and is a CYP1A2 (weak) and UGT1A4 inducer. Table 3 summarizes the recommended uses of APs with lopinavir/ritonavir. There are no APs with little to no evidence of clinically significant interaction expected. We recommend olanzapine, with caution and monitoring patients for reduced clinical effect (ritonavir induction of CYP1A2), and risperidone, monitoring for increased AP effects and the risk of QT prolongation and/or TdP. Information about risk ratings, severity and patient management in each database is summarized in Supplement Table 4 . Lexicomp® Drug Interactions and LiverpoolÓ Drug Interaction Group report that there are no significant risks. Remdesivir and Favipiravir are not included in the Micromedex® Solutions Drugs Interactions database. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. The information on risk rating, severity and patient management for each database is summarized in Supplement Table 5 . The authors' consensus recommendation (see Table 1 ) is that brexpiprazole, cariprazine and lurasidone be used with caution. This is the most conservative approach, because they are not included in the LiverpoolÓ database, and therefore, agreement is not possible. Interactions shows no drug-drug interaction with antipsychotics. The summary information about the risk rating, severity and patient management for each database is available in eTable 6 in the Supplement. All antipsychotics are recommended, but clozapine because of hematological risk (risk rating in zone yellow). Anakinra is not included in the LiverpoolÓ Drug Interaction Group. Micromedex® Solutions Drugs Interactions and Lexicomp® Drug Interactions do not report any drug-drug interaction with antipsychotics. Of the 391 studies were screened and assessed for eligibility. After applying inclusion and exclusion criteria (Supplement eFigure 1), only 7 case reports were selected for inclusion. Data from all included studies are summarized in Table 4 . Two case reports are considered highly probable drug interaction according to DIPS, one with lopinavir/ritonavir and quetiapine (with priapism as the clinical outcome), and with ritonavir/indinavir and risperidone (with acute dystonia and tremor exacerbation as the clinical outcome). There were no deaths among the 8 patients, but two fatal outcome, one patient in coma (Risperidone+Ritonavir) and 2 others with Neuroleptic Malignant Syndrome (Ritonavir+Aripiprazole, and Ritonavir+Risperidone), however all of them remitted. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint There was no study or case report about QT prolongation and/or TdP between the drug of our study. According to the DDIs databases and our systematic review, remdesivir, favipiravir, baricinitib, and anakinra may be concomitantly used with antipsychotics by clinicians for managing delirium, agitation or behavioral problems in COVID-19 patients with no risk of drug-drug interaction (except for hematological risk with clozapine and baricinitib reported only in one database). Tocilizumab is quite safe for use in combination with antipsychotics, however, care should be taken with aripirazole, brexpiprazole, cariprazine, haloperidol, lurasidone and quetiapine, because of decreased exposure of APs, and with clozapine because of hematological risk). Tocilizumab binds to and inhibits the proinflammatory cytokine interleukin-6 (IL-6), and IL-6 decreased CYP3A4 mRNA by over 90% 46 . Tocilizumab may restore CYP3A4 activity and thus increase CYP3A4 substrate metabolism. This effect may persist for several weeks following discontinuation of therapy due to the long half-life of tocilizumab. The COVID-19 treatments with the most risk for co-administration with antipsychotics are chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir. Most of the DDIs databases, point out the increased risk of prolonged QT interval with coadministration of chloroquine, hydroxychloroquine, and azithromycin with antipsychotics. Nevertheless, the cardiotoxicity of antimalarial drugs, with the exception of quinidine and halofantrine, which produce clinically significant prolongation of ventricular repolarization, remains to be confirmed 47, 48 . In the present COVID scenario, Borba et al 49 do not recommend the highest chloroquine dosage for patients critically ill with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. Risk of prolonged QTc (over 500 milliseconds) was higher in patients receiving high doses (600 mg twice daily for 10 days) than a low-dosage group (450 mg twice on Day 1 followed by once daily for four days), 18.9% versus 11.1%, respectively. It is worth mentioning that all patients were also receiving azithromycin, and nearly all were receiving oseltamivir (both also prolong QT interval) 50 . Although treatment with hydroxychloroquine, azithromycin, or both, was not compared with either treatment, in 1438 hospitalized patients with COVID- 19, it was not significantly associated with differences in in-hospital mortality 51 . In addition, grading antipsychotics by torsadogenic risk is not a simple issue, and attributable risk varies depending on the source. 23,52 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint Our work also suggests that the coadministration of protease inhibitors, such as lopinavir/ritonavir, with APs should be cataloged as the most problematic combination, because of the CYP DDIs 53 and the risk of QT prolongation and/or TdP. Although none APs seem to be recommended for used in combination with lopinavir/ritonavir, olanzapine might be considered as the safest option according to DDIs databases and also because none case report describing DDI has been reported. Ritonavir decreases systemic exposure to olanzapine through the induction of both CYP1A2 and UGT. Thus, patients on concomitant olanzapine and ritonavir may require higher doses (up to 50% more) of olanzapine to achieve similar plasma concentrations 54,55 The use of drug interaction databases can be a useful clinical tool, but the lack of agreement between them limits their use [56] [57] [58] [59] [60] . Our study reviewed DDIs in 3 databases which fulfill quality criteria 39,40 , and a systematic review of the literature was also dome in search of possible clinical outcomes of these DDIs. The main treatments used internationally for the treatment of COVID-19 were included, as well as most antipsychotics. As limitations of our study, it should be noted that no studies were found beyond clinical cases which examined clinical results of the interaction between the drugs studied, so this information could not be presented. In conclusion, the growing use of antipsychotics in COVID19 patients calls on the urges development evidence-based guidelines that can help clinicians decide on the safest treatment combination and the level of monitoring that would be warranted for each particular patient. The selection of concomitant COVID-19 medications and antipsychotics should be evidence-based and closely monitored. The main interactions between COVID-19 drugs and antipsychotics are the risk of QT prolongation and/or TdP, and CYP interactions. We would like to thank Carmen Jimenez, who encouraged us to start this work. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. HCLQ: Hydroxychloroquine, CLQ: Chloroquine, AZT: Azithromycine, LPV/r: Lopinavir/ritonavir, RDV: Remdesivir, FAV: Favipiravir, TCZ: Tocilizumab, BAR; Baricinitib, ANK: Anakinra TdP Risk: Risk Categories for Drugs that prolong QT and induces Torsade de Pointes (TdP): Known Risk of TdP (these drugs prolong the WT interval and are clearly associated with a known risk of TdP, even when taken as recommended), Possible Risk of TdP (these drugs can cause QT prolongation but currently lack evidence for risk of TdP when taken as recommended), Conditional Risk of TdP (these drugs are associated with TdP but only under certain conditions of their use (e.g. excessive dose, in patients with conditions such as hypokalemia, or when taken with interacting drugs) or by creating conditions that facilitate or induce TdP (e.g. by inhibiting metabolism of QT-prolonging drugs or by causing an electrolyte disturbance that induce TdP), Not classified (this drug has been reviewed but the evidence available at this time did not result in a decision for it to be placed in any of the four QT risk categories. This is not an indication that this drug is free of a risk of QT prolongation or torsades de pointes since it may not have been adequately tested for these risks in patients) according to CredibleMeds®. Brexpiprazole, Capriprazine (a) Potential increased exposure of Aps, (b) Additional interaction: Phenothiazides/Antimalarial (increased serum concentration of phenothiazines), (c) Additional interaction: Risk Hematological toxicity, (d) Paliperidone and Risperidone (P-glycoprotein/ABCB1 Substrates) and Azithromycin (P-glycoprotein/ABCB1 inhibitors), (e) Torsade de Pointes (TdP) Risk Categories by QTDrugs de CredibleMeds®: Known Risk of TdP (these drugs prolong the WT interval and are clearly associated with a known risk of TdP, even when taken as recommended), Possible Risk of TdP (these drugs can cause QT prolongation but currently lack evidence for risk of TdP when taken as recommended), Conditional Risk of TdP (these drugs are associated with TdP but only under certain conditions of their use (e.g. excessive dose, in patients with conditions such as hypokalemia, or when taken with interacting drugs) or by creating conditions that facilitate or induce TdP (e.g. by inhibiting metabolism of QT-prolonging drugs or by causing an electrolyte disturbance that induce TdP), Not classified (this drug has been reviewed but the evidence available at this time did not result in a decision for it to be placed in any of the four QT risk categories. This is not an indication that this drug is free of a risk All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint of QT prolongation or torsades de pointes since it may not have been adequately tested for these risks in patients) △There is not enough information to assign the antipsychotic to any of the previous risk rating categories, the recommendations reflect the more conservative approach. This recommendation to be taken with caution; • No antipsychotics in this category All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted June 8, 2020. . https://doi.org/10.1101/2020.06.04.20122416 doi: medRxiv preprint Table 3 . Drug-Drug interaction between Antipsychotics and Lopinavir/Ritonavir National Institute for Health and Care Excellence (NICE) in collaboration with NHS England and NHS Improvement. Managing COVID-19 symptoms (including at the end of life) in the community: summary of NICE guidelines Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease Neurologic Features in Severe SARS-CoV-2 Infection The impact of delirium in the intensive care unit on hospital length of stay Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit The Cost of ICU Delirium and Coma in the Intensive Care Unit Patient Delirium: a missing piece in the COVID-19 pandemic puzzle ICU delirium -a diagnostic and therapeutic challenge in the intensive care unit Comparative efficacy and safety of therapy for the behavioral and psychological symptoms of dementia: a systemic review and Bayesian network meta-analysis Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Chloroquine and hydroxychloroquine in the context of COVID-19. Drugs Context. 2020 Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation Van Den Eede F. Efficacy and Tolerability of Atypical Antipsychotics in the Treatment of Delirium: A Systematic Review of the Literature Use and safety of antipsychotics in behavioral disorders in elderly people with dementia Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis Atypical antipsychotic drugs and the risk of sudden cardiac death Drug-drug interactions associated with second-generation antipsychotics: considerations for clinicians and patients Pharmacokinetic enhancement of protease inhibitor therapy Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Treatment options for COVID-19: The reality and challenges Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome. ACR Open Rheumatol Lexicomp® Interactions Module Calidad estructural de las bases de datos de interacciones Evaluation of resources for analyzing drug interactions Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement Rayyan-a web and mobile app for systematic reviews Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses Gene-specific effects of inflammatory cytokines on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes Cardiotoxicity of antimalarial drugs The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs: a systematic review Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial Caution Needed on the Use of Chloroquine and Hydroxychloroquine for Coronavirus Disease Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State Torsadogenic risk of antipsychotics: combining adverse event reports with drug utilization data across Europe Mechanism-based inactivation of CYP3A by HIV protease inhibitors Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers Drug-Drug Interactions With Antiviral Agents in People Who Inject Drugs Requiring Substitution Therapy Concordance of severity ratings provided in four drug interaction compendia Lack of drug interaction conformity in commonly used drug compendia for selected at-risk dermatologic drugs Acknowledgments UPDURAP of the UPDURAP are listed in the. Disagreement Among Drug Compendia on Inclusion and Ratings of Drug-Drug Interactions Comparative assessment of four drug interaction compendia A comparison of potential psychiatric drug interactions from six drug interaction database programs Antipsychotic-induced priapism in an HIV patient: a cytochrome P450-mediated drug interaction Increased aripiprazole concentrations in an HIVpositive male concurrently taking duloxetine, darunavir, and ritonavir Clinically significant adverse events from a drug interaction between quetiapine and atazanavir-ritonavir in two patients Reversible coma caused by risperidone-ritonavir interaction Extrapyramidal symptoms with ritonavir/indinavir plus risperidone Neuroleptic malignant syndrome associated with use of risperidone, ritonavir, and indinavir: a case report Potential interaction which may require a dose adjustment, close monitoring, choosing alternative agents in 2 or more database, Zone Yellow: Potential interaction likely to be of weak intensity. Additional action/monitoring or dose adjustment unlikely to be required in 2 or more database, Zone Green: Little to no evidence of clinically significant interaction expected in 2 or more database △The more conservative approach. There is not enough information to assign the antipsychotic to any of the previous categories. This recommendation to be taken with caution; (*) Only classified in one database but in this category Type of interaction: ♥♥ QT-Prolonging agents Potential increased/decreased exposure of APs