Magnesium and major depression

New paradigms for treatment‐resistant depression

“…In order to address this question, one strategy to mildly modulate central NMDAR activity is to target its voltage‐dependent magnesium (Mg 2+ ) block. For example, feeding mice a low Mg 2+ –containing diet (50–120 mg/kg food) for three weeks causes a reduction in brain and plasma Mg 2+ levels compared with mice on a control diet; a similar condition was also reported in some, though not all, patients with depression . Although Mg 2+ ‐deficient animals appear normal (e.g., they have shiny fur and normal gain in body weight, circadian activity rhythm, and locomotor performances), their body temperature increased .…”

“…Using unbiased proteomics, only four out of more than 300 soluble proteins analyzed were identified as altered in the amygdala following Mg 2+ ‐deficiency. Among these, changes in N,N ‑dimethylarginin‐dimethylaminohydrolase 1 and manganese superoxide dismutase point toward the possibility of upregulated NMDAR/nitric oxide (NO) pathway signaling . Furthermore, preliminary data from Sartori's group shows that the Mg 2+ ‐deficiency–induced enhanced depression‐related behavior is blocked after a single application of the NMDAR antagonist ketamine, as well as in heterozygous neuronal nitric oxide synthase knockout mice (unpublished data).…”

“…Sartori also reported that in Mg 2+ ‐deficient mice, increased transcription of the pre–pro‐corticotropin releasing hormone in the paraventricular hypothalamic nucleus leads to increased release of the stress hormones ACTH and aldosterone, indicating dysfunction in the neuroendocrine stress axis that is known to control mood and emotions as well as the immune system. Correspondingly, immune responses have been shown to be altered in Mg 2+ ‐deficient rodents . Chronic antidepressant treatment normalizes the Mg 2+ ‐deficiency–induced dysfunctions in the neuroendocrine system and NMDAR/NO signaling pathways in parallel with the observed behavioral effects …”

“…Correspondingly, immune responses have been shown to be altered in Mg 2+ ‐deficient rodents . Chronic antidepressant treatment normalizes the Mg 2+ ‐deficiency–induced dysfunctions in the neuroendocrine system and NMDAR/NO signaling pathways in parallel with the observed behavioral effects …”

“…While these results have been replicated in different laboratories, the anxiogenic effects of hypomagnesemia in humans seem to be more variable, reflecting the clinical setting where a comorbid anxiety disorder is diagnosed in about 60% of depressed individuals. Chronic oral administration of antidepressant drugs (paroxetine, desipramine, or St. John's Wort) normalizes the enhanced depression‐ and/or anxiety‐related behavior displayed by Mg 2+ ‐deficient mice …”