Is major depressive disorder a metabolic encephalopathy?

Abstract

Metabolic encephalopathy is an acute disturbance in cellular metabolism in the brain evoked by conditions of hypoxia, hypoglycaemia, oxidative stress and/or inflammation. It usually develops acutely or subacutely and is reversible if the systemic disorder is treated. If left untreated, however, metabolic encephalopathy may result in secondary structural damage to the brain. Most encephalopathies are present with neuropsychiatric symptoms, one in particular being depression. However, mood disorders are often co-morbid with cardiovascular, liver, kidney and endocrine disorders, while increasing evidence concurs that depression involves inflammatory and neurodegenerative processes. This would suggest that metabolic disturbances resembling encephalopathy may underscore the basic neuropathology of depression at a far deeper level than currently realized. Viewing depression as a form of encephalopathy, and exploiting knowledge gleaned from our understanding of the neurochemistry and treatment of metabolic encephalopathy, may assist in our understanding of the neurobiology of depression, but also in realizing new ideas in the pharmacotherapy of mood disorders.

Azure B and a synthetic structural analogue of methylene blue, ethylthioninium chloride, present with antidepressant-like properties

“…As an extension of these actions, MB has shown promising antidepressant and anxiolytic qualities in bipolar disorder (Naylor et al, 1986(Naylor et al, , 1987Alda et al, 2011). Considering the role of mitochondrial dysfunction and oxidative stress in the pathology of depression, MB's ability to enhance mitochondrial function by cycling between the reduced leucomethylene blue (leucoMB) and the oxidized MB states will inhibit the production of superoxide by competing with molecular oxygen (Atamna and Kumar, 2010;Oz et al, 2009;Visarius et al, 1997;Kelner et al, 1988;Salaris et al, 1991), and in this way counter the atrophic changes that complicate this illness (Duman and Monteggia, 2006;Harvey, 2008;Krishnan and Nestler, 2008).…”

“…Despite the availability of a variety of antidepressants, the efficacy of current treatment regimens remains inadequate and a significant proportion of patients fail to respond to first-line therapy, or do not reach complete remission (Sartorius et al, 2007). The available antidepressant agents target one or more of the monoaminergic systems, while new evidence suggests that depression is not a single transmitter illness and that a number of pathological processes may be involved (Manji et al, 2003;D'Sa and Duman, 2002;Nestler et al, 2002;Duman and Monteggia, 2006;Harvey, 2008;Krishnan and Nestler, 2008), in particular pathways involved in mitochondrial function, redox regulation and cell viability (Fattal et al, 2006;Harvey, 2008). These shortcomings prompt the design of novel multimodal antidepressants and the identification of new antidepressant targets with improved response rates as well as safety profiles.…”

Appraisal of ozone as biologically active molecule and experimental tool in biomedical sciences

“…Our data indicate that acute imipramine treatment can yield some protection against oxidative stress conditions induced by ozone exposure, which has important implications for how imipramine induces its antidepressant effects. Indeed, actions on cellular redox represent a novel target for antidepressant action (Harvey, 2008). The ozone inhalation model can, therefore, be used to study the role of redox pathways in depression and antidepressant action.…”

Metabolic and Glutathione Redox Markers Associated with Brain-Derived Neurotrophic Factor in Depressed African Men and Women: Evidence for Counterregulation?

“…Indeed, there is increasing evidence for an interaction between major depression and metabolic disorders and between depression and cardiovascular disorders [13,14,15,16,17,18]. Although alterations in brain serotonergic transmission and/or cortisol secretion play a role in the pathogenesis of depression, it would appear that altered neuroimmune mechanisms and altered neurotrophin support play a more dominant causal role [19,20,21]. Likewise, while the pathways linking depression and cardiovascular disease [22] are complex, it is clear that sympathetic nervous system hyperactivity, inflammation, hemostasis, and altered metabolic and cardiac autonomic control are implicated [21,23,24,25].…”