Melatonin Use Rationale for Depression and Dementia

Depression (and dementia) is likely due to metabolically unhealthy cells that have reduced number and reduced functioning mitochondria that result from genes being turned off by epigenetic methylation of gene promoter sites.

Considered here is MELATONIN that declines with age and its positive and protective effect on cell metabolic health.

Melatonin increases Sirt1.

Melatonin directly and indirectly reduces inflammation.

Melatonin is integral to all known forms of DNA repair for nuclear and mitochondrial genes.

Melatonin is integral for correct RNA splicing.

Melatonin turns on methylated genes through HDAC inhibition and direct antioxidant effect.

Melatonin reduces oxidative and nitrosative stress.

Melatonin rich cells have increased number and increased function of mitochondria.

Melatonin rich cells have NO and hTert in excess of H2O2 and have lower level pulses of ROS because of increased expression of antioxidant enzymes.

Melatonin rich cells have homeostasis of mitochondrial fission and fusion proteins and the mitochondria are not skinny or fat but lean and fit.

Melatonin rich cells have reduced markers of cell senescence.

Melatonin rich cells have increased functional integrity and function within tissues and organs.

Melatonin rich cells express lower levels of il-beta 1, caspase and downstream homocysteine and C-reactive protein.

Melatonin rich cells have efficient autophagy with fewer autophagosomes because of healthy maintenance and reduced oxidation and protein  and glycosylation aggregates.

Melatonin rich cells cleave APP in a nontoxic way and beta amyloid is reduced in production and cleared.

Melatonin rich cell state occurs in the young and melatonin poor state occurs with aging.

Cognitive and affective decline is caused by lack of metabolic and gene support that could be improved by supplemental melatonin and its functional mimics.

Melatonin should therefore reverse and prevent depression and dementia in the long term.  Antidepressants are  recommended for 6-18 months of initial therapy duration.

Dale Bredesen, MD reports dementia reversal over 6 months in his treatment algorithm.

I conjecture that melatonin should be adjunctive for initial therapy of MDD and provide monotherapy for prevention and maintenance and over all make our current therapies more effective and more sustaining

http://www.sciencedirect.com/science/article/pii/S0278584616303839

Linking the biological underpinnings of depression: Role of mitochondria interactions with melatonin, inflammation, sirtuins, tryptophan catabolites, DNA repair and oxidative and nitrosative stress, with consequences for classification and cognition - ScienceDirect

The pathophysiological underpinnings of neuroprogressive processes in recurrent major depressive disorder (rMDD) are reviewed. A wide array of biochemical processes underlie MDD presentations and their shift to a recurrent, neuroprogressive course, including: increased immune-inflammation, tryptophan catabolites (TRYCATs), mitochondrial dysfunction, aryl hydrocarbonn receptor activation, and oxidative and nitrosative stress (O&NS), as well as decreased sirtuins and pathway activity. These biochemical changes may have their roots in central, systemic and/or peripheral sites, including in the gut, as well as in developmental processes, such as prenatal stressors and breastfeeding consequences. Consequently, conceptualizations of MDD have dramatically moved from simple psychological and central biochemical models, such as lowered brain serotonin, to a conceptualization that incorporates whole body processes over a lifespan developmental timescale. However, important hubs are proposed, including the gut-brain axis, and mitochondrial functioning, which may provide achievable common treatment targets despite considerable inter-individual variability in biochemical changes. This provides a more realistic model of the complexity of MDD and the pathophysiological processes that underpin the shift to rMDD and consequent cognitive deficits. Such accumulating data on the pathophysiological processes underpinning MDD highlights the need in psychiatry to shift to a classification system that is based on biochemical processes, rather than subjective