Depression is a leading cause of disability globally, with a prevalence of 3.8% among the whole population, 5% of the adult population, and 5.7% of the elderly population over 60 years of age. There is evidence that depression is linked to certain neurodegenerative diseases, one being Alzheimer’s disease (AD). The efficacy of conventional antidepressants to treat depression in AD is conflicting, especially regarding selective serotonin reuptake inhibitors (SSRIs). A recent systemic review and meta-analysis of 25 randomized controlled trials including fourteen antidepressant medications showed no high efficacy in treating AD patients’ symptoms. However, ketamine, a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist, can mediate a wide range of pharmacological effects, including neuroprotection, anti-inflammatory and anticancer properties, multimodal analgesia, and treatment of depression, suicidal attempts, and status epilepticus. Esketamine, which is ketamine formulated as a nasal spray, was approved by the Federal Drug Administration (FDA) in March 2019 as an adjuvant drug to treat treatment-resistant depression. NMDA receptor antagonists treat AD through offsetting AD-related pathological stimulation of subtypes of glutamate receptors in the central nervous system. Recent clinical findings suggest that ketamine may provide neuroprotection and reduce neuropsychiatric symptoms associated with AD. In the present investigation, we evaluate the potential role of ketamine and its postulated mechanism in AD management.

Vitamin D receptors are expressed in many organs and tissues, which suggests that vitamin D (VD) affects physiological functions beyond its role in maintaining bone health. Deficiency or inadequacy of 25(OH)VD is widespread globally. Population studies demonstrate that a positive association exists between a high incidence of VD deficiency and a high incidence of chronic diseases, including dementia, diabetes, and heart disease. However, many subjects have difficulty achieving the required circulating levels of 25(OH)VD even after high-dose VD supplementation, and randomized controlled clinical trials have reported limited therapeutic success post-VD supplementation. Thus, there is a discordance between the benefits of VD supplementation and the prevention of chronic diseases in those with VD deficiency. Why this dissociation exists is currently under debate and is of significant public interest. This review discusses the downregulation of VD-metabolizing genes needed to convert consumed VD into 25(OH)VD to enable its metabolic action exhibited by subjects with metabolic syndrome, obesity, and other chronic diseases. Research findings indicate a positive correlation between the levels of 25(OH)VD and glutathione (GSH) in both healthy and diabetic individuals. Cell culture and animal experiments reveal a novel mechanism through which the status of GSH can positively impact the expression of VD metabolism genes. This review highlights that for better success, VD deficiency needs to be corrected at multiple levels: (i) VD supplements and/or VD-rich foods need to be consumed to provide adequate VD, and (ii) the body needs to be able to upregulate VD-metabolizing genes to convert VD into 25(OH)VD and then to 1,25(OH)2VD to enhance its metabolic action. This review outlines the association between 25(OH)VD deficiency/inadequacy and decreased GSH levels, highlighting the positive impact of combined VD+LC supplementation on upregulating GSH, VD-metabolizing genes, and VDR. These effects have the potential to enhance 25(OH)VD levels and its therapeutic efficacy.