Exploring the mechanisms of action of the antidepressant effect of the ketogenic diet.

The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms - for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.

Integrating digital phenotyping in clinical characterization of individuals with mood disorders.

Major Depressive Disorder (MDD) and bipolar disorder (BD) are still under recognized and undertreated, especially in primary care settings. One of the challenges faced by clinicians is the remarkable inter-individual variability among patients with these conditions. In addition, each patient with MDD and BD experiences a unique pattern of longitudinal changes across time, i.e., intra-individual variability can also be problematic. The immense amount of data generated and collected through the use of smartphones or personal devices offers an opportunity to obtain continuous and reliable information on each individual's behavior, a less burdensome way to capture both intra and inter-individual variability over time. Digital phenotypes (DP) are a promising strategy to be integrated with other "Omics" platforms for prediction of relevant outcomes in mood disorders, including but not restricted to, relapse, recurrence, cognitive decline and functional impairment. Despite existing limitations and some skepticism, digital phenotyping represents a field in great expansion and might eventually constitute a feasible strategy in biomarkers research for mood disorders.

Association between diabetes and mood disorders and the potential use of anti-hyperglycemic agents as antidepressants.

Epidemiological and mechanistic studies support the association between Diabetes Mellitus and mood disorders, such as Major Depressive Disorder and Bipolar Disorder. This association is especially relevant in specific domains of depressive psychopathology, such as disturbances in reward systems and cognitive functions. Several anti-hyperglycemic agents have demonstrated effects on depressive symptoms and cognitive decline and this efficacy is probably the result of an action in shared brain targets between these two groups of conditions. These medications include subcutaneous insulin, intranasal insulin, metformin, and liraglutide. The study of the mechanisms involved in the relationship between Diabetes Mellitus and mood disorders offers a new avenue of investigation, and this understanding can be applied when examining whether antidiabetic agents can be repurposed as antidepressants and mood stabilizers. The objective of this narrative review is to critically appraise the literature surrounding drugs commonly used as anti-hyperglycemic agents and their effects on the brain, while discussing their potential as a new treatment for mental illnesses, and specifically, mood disorders.