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.