Mental health is closely linked to physical health. Depression (e.g., major depression) is highly prevalent worldwide and a major cause of disability. In a subgroup with treatment-resistant depression, standard pharmacotherapy interventions provide small if any incremental improvement in patient outcomes and may also require the application of an alternate approach. Therefore, in addition to the standard pharmacotherapies prescribed, patients will also be advised on the benefits of psychological counseling, electroconvulsive therapy, and transcranial magnetic stimulation or increasing physical activity and reducing harmful substance consumption. Numerous nutraceuticals have a beneficial role in treatment-resistant depression and include, herbal medicines of which Hypericum perforatum is the best studied, omega-3 fatty acid preparations, S-Adenosyl-L-Methionine (SAMe), various mineral formulations (e.g., magnesium) and folate (singly or in combination with B group vitamins) are prescribed to a lesser extent. Furthermore, a largely neglected area of research activity has been the role of live probiotic cultures that contribute to repairing dysbiosis (a leaky gut barrier abnormality) in the gastrointestinal tract (GIT). In this commentary, we build a hypothesis that in addition suggests that GIT metabolites that are elaborated by the microbiome cohort may provide novel and significant avenues for efficacious therapeutic interventions for mood disorders. We posit that the microbiome in the gastrointestinal tract is implicit as an important participant for the amelioration of adverse mood conditions via the diverse metabolic activities provided by live beneficial bacteria (probiotics) as an active adjuvant treatment. This activity is in part triggered by a controlled release of reactive oxygen species (ROS) and hence further questions the antioxidant/oxidative stress postulate.