Concerning the first stage, these include a paucity of relevant studies in patients with depression, access to a limited number of databases for the literature search, difficulties in extrapolating findings from animal models of depression, the indirect nature of much of the available evidence linking motilin to the pathophysiology of depression, the lack of replication of the available positive findings and the lack of research linking motilin to those mechanisms, particularly alterations in the microbiome, which are considered to be more relevant in depression. This evidence concerns the gene MLN and depressive symptom measurement.