Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis
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Abstract
Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters.
Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed.
Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher’s Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients ( p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,“inflammatory bowel disease (IBD)” (the most significant pathway with a p adj of 0.00021), “Th1 and Th2 cell differentiation” and “B cell receptor signaling pathway”) that have been also associated with COVID19 clinical outcome.
Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.
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SciScore for 10.1101/2020.12.05.20244590: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Conforming to international standards for research ethics, this study was approved by the Cantabria Ethics Institutional Review Board (IRB).
Consent: Patients meeting inclusion criteria for a first episode of psychosis (drug-naïve) and their families provided written informed consent to be included in the study.Randomization After informed consent was signed, patients were included in a prospective, randomized, flexible-dose, open-label study (Crespo-Facorro et al., 2017; Mayoral Van-Son et al, 2020). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Sequence … SciScore for 10.1101/2020.12.05.20244590: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: Conforming to international standards for research ethics, this study was approved by the Cantabria Ethics Institutional Review Board (IRB).
Consent: Patients meeting inclusion criteria for a first episode of psychosis (drug-naïve) and their families provided written informed consent to be included in the study.Randomization After informed consent was signed, patients were included in a prospective, randomized, flexible-dose, open-label study (Crespo-Facorro et al., 2017; Mayoral Van-Son et al, 2020). Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Software and Algorithms Sentences Resources Sequence files were aligned to the GRCh38 human reference genome (Gencode release 25) using the STAR aligner(Dobin et al., 2013; Harrow et al., 2012) STARsuggested: (STAR, RRID:SCR_015899)These data were analyzed with RaNA-Seq (Prieto & Barrios, 2019) cloud platform and differential expression genes were detected by means of DESeq2 (Love et al., 2014) cloud using a Wald test, a parametric fit type and setting an adjusted p-value cutoff of 0.01. 2.6 Statistical and bioinformatic Analysis: Statistical significance of differential expression co-occurrence between COVID and Aripiprazole studies was calculated with a Fisher Exact test. DESeq2suggested: (DESeq, RRID:SCR_000154)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: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT02200588 Enrolling by invitation Longitudinal Long-term Study (10 Years) of the Sample of Fir… NCT03481465 Enrolling by invitation Searching for Early Biomarkers of Long-term Hepatic, Metabol… NCT03476473 Enrolling by invitation Early Detection of Respiratory Disorders in Psychosis 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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