The Resistant Depression Response to Esketamine Assessing Metabolomics (ReDREAM) Project-Untargeted Metabolomics to Identify Biomarkers of Treatment Response to Intranasal Esketamine in Individuals with Treatment-Resistant Depression: A Study Protocol.

Treatment-resistant depression (TRD) affects about 20-30% of people with major depressive disorder. Esketamine nasal spray was approved for TRD in 2019, but its mechanisms of action remain unclear. This protocol describes the ReDREAM project, an observational, prospective study that will use metabolomics to identify metabolic biosignatures associated with response to esketamine. Sixty people with TRD from three Italian clinical sites will receive esketamine nasal spray twice weekly for four weeks (induction phase), then once weekly for four more weeks (maintenance phase). The study will test correlations between baseline metabolic profile and depressive symptom improvement at weeks 4 and 8, and explore metabolic differences between responders and non-responders. Hypothesized involvement includes energy metabolism, amino acid metabolism, urea cycle, and nitric oxide synthesis.

Study at a glance

Abstract

Treatment-resistant depression (TRD) affects around 20-30% of people with major depressive disorder. In 2019, esketamine nasal spray was approved for TRD by both the US Food and Drug Administration and the European Medicines Agency. While its clinical efficacy and safety are proven, the mechanisms underlying its antidepressant effect remain unclear. The use of metabolomics may allow understanding the metabolic effects of esketamine and predicting biological features associated with clinical response in TRD. Nonetheless, there is a lack of studies exploring the predictive value of metabolomics. The Resistant Depression Response to Esketamine Assessing Metabolomics (ReDREAM) project aims at identifying metabolic biosignatures that may represent novel correlates of response to esketamine treatment. This is the protocol of an observational, prospective study. We plan to select 60 people with TRD from 3 clinical sites in Italy. The participants will be administered with esketamine nasal spray, following standard clinical practice, twice a week for 4 weeks ("induction phase"), then once a week for 4 additional weeks ("maintenance phase"). We will test the correlations between baseline metabolic profile and depressive symptom improvement at study endpoints (weeks 4 and 8) and we will explore the likelihood of different metabolic phenotypes between responders and non-responders. An involvement of energy metabolism, amino acid metabolism, urea cycle, and nitric oxide synthesis in response to treatment with esketamine nasal spray is hypothesized. Unbiased data from untargeted metabolomics associated with clinical changes after esketamine treatment may contribute to define new paradigms for precision psychiatry-oriented, personalized care of TRD.