Understanding treatment-resistant depression using "omics" techniques: A systematic review

Background: Treatment-resistant depression (TRD) results in huge healthcare costs and poor patient clinical outcomes. Most studies have adopted a "candidate mechanism" approach to investigate TRD pathogenesis, however this is made more challenging due to the complex and heterogeneous nature of this condition. Highthroughput "omics" technologies can provide a more holistic view and further insight into the underlying mechanisms involved in TRD development, expanding knowledge beyond already-identified mechanisms. This systematic review assessed the information from studies that examined TRD using hypothesis-free omics techniques.Methods: PubMed, MEDLINE, Embase, APA PsycInfo, Scopus and Web of Science databases were searched on July 2022. 37 human studies met the eligibility criteria, totalling 17,518 TRD patients, 571,402 healthy controls and 62,279 non-TRD depressed patients (including antidepressant responders and untreated MDD patients).Results: Significant findings were reported that implicate the role in TRD of various molecules, including polymorphisms, genes, mRNAs and microRNAs. The pathways most commonly reported by the identified studies were involved in immune system and inflammation, neuroplasticity, calcium signalling and neurotransmitters.Limitations: Small sample sizes, variability in defining TRD, and heterogeneity in study design and methodology.Conclusions: These findings provide insight into TRD pathophysiology, proposing future research directions for novel drug targets and potential biomarkers for clinical staging and response to antidepressants (citalopram/ escitalopram in particular) and electroconvulsive therapy (ECT). Further validation is warranted in large prospective studies using standardised TRD criteria. A multi-omics and systems biology strategy with a collaborative effort will likely deliver robust findings for translation into the clinic.