(469) Gene Expression Signatures of Fluoxetine Response: Systematic Review and Meta-Analysis

Objective : Selecting the right antidepressant for a patient with Major Depressive Disorder (MDD) remains a challenge, and some have turned to genomic (and other "omic") data to identify a recommended therapy. In this work, we conducted a systematic review and meta-analysis to identify gene expression patterns associated with response or resistance to antidepressants.

Methods: A keyword search of the Gene Expression Omnibus (GEO) database was used to identify datasets profiling gene expression in patients or rodent models treated with fluoxetine. Results were excluded if not conducted in the context of depression or anxiety, in an irrelevant tissue type, or if there were fewer than three samples per group. Each included dataset was systematically re-analyzed for differential gene expression comparing responders against non-responders, and then summarized at the level of biological pathways using Gene Set Enrichment Analysis. Results were meta-analyzed across datasets using P value combination methods to identify those that are consistently differentially expressed across comparisons.

Results: 74 datasets were manually screened for the exclusion criteria, resulting in 20 selected for inclusion: 18 in rodents, and two in human patients with MDD. Of these, six studies included a determination of clinical or behavioral response. 19 biological pathways were identified as consistently differentially expressed in responders vs. non-responders, including toll-like receptor (TLR) pathways, the NF-κB signaling pathway, and other immune pathways, in addition to two ribosomal pathways.

Conclusions: This meta-analysis confirms the importance of the immune system in depression and antidepressant response, and it provides new hints for pathways warranting further investigation. Additional large-cohort studies applying other ‘omics technologies will allow us to better understand the heterogeneity and intricacies of antidepressant response.