F47. TRANSCRIPTIONAL PROFILING OF PERIPHERAL BLOOD IN DEPRESSIVE PATIENTS TREATED WITH ESKETAMINE NASAL SPRAY

• Published in: European neuropsychopharmacology 2023-10, Vol.75, p.S246-S247
• Main Authors: Li, Qingqin, Wu, Chun, Azhar, Nabil, Popova, Vanina, Fedgchin, Maggie, Fu, Dong-Jing, Ionescu, Dawn, Canuso, Carla, Drevets, Wayne
• Format: Article
• Language: English
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2023.08.435

Esketamine nasal spray is indicated for the treatment of adults with treatment-resistant depression (TRD) and major depressive disorder with suicidal ideation or behavior (MDSI). We assessed the blood transcriptional signature from patients participating in the Phase 3 trials testing the efficacy and safety of esketamine. We assessed the transcriptional signature in blood samples from patients with TRD or MDSI receiving esketamine or placebo combined with an oral antidepressant to understand the baseline molecular correlate of treatment response. The mRNA-Seq data from 695 subjects from three TRD studies and 402 subjects from two MDSI studies were generated. Differential expression analysis was performed to identify transcripts at baseline correlating with esketamine and placebo response, respectively. Meta-analysis was performed to identify consistent transcripts across the TRD/MDSI studies or among all patients. The expression levels of thirteen transcripts measured at baseline correlated with the antidepressant response to esketamine in the patients with TRD. The most significant finding (p = 5.34 × 10-8, adjusted p-value=0.0005) was a long non-coding RNA (lincRNA) LINC0272. In blood, LINC01272 is expressed in myeloid cells that are implicated in innate immune response and myeloid pro-inflammatory response, supporting the hypothesis that pretreatment inflammation is associated with the treatment response to esketamine. This finding appears to be specific to the patients with TRD, as LINC01272 association is weaker if meta-analyzing with the studies in patients with MDSI, HNRNPA1 remains significant at adjusted p < 0.1 in a meta-analysis across 5 studies. No transcript passed study wide significant threshold for the placebo analysis. 380 transcripts that positively co-expressed (r > 0.25) with LINC01272, while 233 transcripts that negatively co-expressed with LINC01272 in 1034 samples. The positively correlated genes are enriched in gene sets involved in the innate immune system (p = 6.11 × 10-21, q-value = 1.34 × 10-17), neutrophil degranulation (p = 5.2 × 10-14, q-value = 5.72 × 10-11), chemokine signaling pathway (p = 5.15 × 10-8. q-value = 1.62 × 10-5), signaling by interleukins (p = 3.45 × 10-7, q-value = 6.32 × 10-5), vesicle-mediated transport (p = 6.33 × 10-8, q-value = 1.62 × 10-5), and Fc gamma receptor (FCGR) dependent phagocytosis (p = 1.79 × 10-7, q-value = 4.37 × 10-5). The negatively correlated genes are enriched in gene sets involved in c