Gut Hormones as Potential Therapeutic Targets or Biomarkers of Response in Depression: The Case of Motilin.

Ravi Philip Rajkumar

doi:10.3390/life11090892

Abstract

Recent research has identified the gut–brain axis as a key mechanistic pathway and potential therapeutic target in depression. In this paper, the potential role of gut hormones as potential treatments or predictors of response in depression is examined, with specific reference to the peptide hormone motilin. This possibility is explored through two methods: (1) a conceptual review of the possible links between motilin and depression, including evidence from animal and human research as well as clinical trials, based on a literature search of three scientific databases, and (2) an analysis of the relationship between a functional polymorphism (rs2281820) of the motilin (MLN) gene and cross-national variations in the prevalence of depression based on allele frequency data after correction for potential confounders. It was observed that (1) there are several plausible mechanisms, including interactions with diet, monoamine, and neuroendocrine pathways, to suggest that motilin may be relevant to the pathophysiology and treatment of depression, and (2) there was a significant correlation between rs2281820 allele frequencies and the prevalence of depression after correcting for multiple confounding factors. These results suggest that further evaluation of the utility of motilin and related gut peptides as markers of antidepressant response is required and that these molecular pathways represent potential future mechanisms for antidepressant drug development.

Highlights

Depression is one of the most common mental disorders, affecting over 25 million individuals worldwide, with an estimated 12-month prevalence of 5.5–6% and a lifetime prevalence of 11–15% across various countries [1,2]
Medications acting on both monoamine and melatonin receptors have been approved for the treatment of depression, and though effective, they do not appear to offer a significant advantage over older drugs in terms of efficacy [11]
Plasma motilin showed a tendency to normalize following treatment in these patients [84]. These results suggest that either excessive or deficient functioning of the HPT axis may be associated with alterations in the motilin levels, which may be related to the frequent comorbidity between thyroid disorders and depression [85,86]

Summary

Introduction

Depression is one of the most common mental disorders, affecting over 25 million individuals worldwide, with an estimated 12-month prevalence of 5.5–6% and a lifetime prevalence of 11–15% across various countries [1,2]. Though effective treatments for depression have been developed, the efficacy of pharmacological treatments is modest in many patients [4], with only half of the patients showing a significant response and one third responding completely to a given drug [5]. Contemporary models of depression, while recognizing the importance of these mechanisms, have identified a variety of other molecular and cellular processes involved in the pathogenesis of this disorder These include changes in the neuroendocrine and stress-related pathways, alterations in neural plasticity and neurogenesis, activation of immune-inflammatory pathways and the involvement of transmitters other than monoamines, such as glutamate, gamma–aminobutyric acid (GABA) and neuropeptides [12,13,14,15]. The efficacy of novel antidepressants such as ketamine, which targets glutamatergic receptors, and brexanolone, a progesterone derivative acting through GABA receptors, provides some support for this perspective [17,18]

Methods

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Discussion

Conclusion