Total and ionized calcium and magnesium are significantly lowered in drug-naïve depressed patients: effects of antidepressants and associations with immune activation

Metab Brain Dis. 2019 Oct;34(5):1493-1503. doi: 10.1007/s11011-019-00458-5. Epub 2019 Jul 10.


Major depressive disorder (MDD) is associated with alterations in calcium (Ca) and magnesium (Mg), as well as circulating pro- and anti-inflammatory cytokines. Anti-inflammatory drugs are commonly used as adjuvant treatments for MDD. However, no studies examined the effects of a combinatorial treatment with sertraline and ketoprofen, an anti-inflammatory drug, on Ca and Mg levels in MDD. The present study examined a) differences in both cations between drug-naïve MDD patients and controls, and b) the effects of sertraline and ketoprofen on Ca and Mg (both total and ionized). In the same patients, we also examined the associations between both cations and IL-1β, IL-4, IL-6, IL-18, IFN-γ, TGF-β1, zinc, and indoleamine 2,3-dioxygenase (IDO). Clinical improvement was assessed using the Beck Depression Inventory-II (BDI-II) at baseline and after follow up for 2 months. Serum Ca and Mg (total and ionized) were significantly lower in MDD patients as compared with controls, while treatment significantly increased calcium but decreased magnesium levels. There were significant and inverse correlations between the BDI-II scores from baseline to endpoint and Ca (both total and ionized), but not Mg, levels. The effects of calcium on the BDI-II score remained significant after considering the effects of zinc, IDO and an immune activation z unit-weighted composite score based on the sum of all cytokines. There was a significant and inverse association between this immune activation index and calcium levels from baseline to endpoint. In conclusion, lowered levels of both cations play a role in the pathophysiology of major depression. Antidepressant-induced increases in Ca are associated with clinical efficacy and attenuation of the immune response. The suppressant effect of antidepressants on Mg levels is probably a side effect of those drugs. New antidepressant treatments should be developed that increase the levels both Ca and Mg. Graphical abstract.

Keywords: Cytokines; Depression; Indoleamine 2,3-dioxygenase; Inflammation; Neuro-immune.

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Calcium / blood*
  • Depressive Disorder, Major / blood*
  • Depressive Disorder, Major / drug therapy
  • Female
  • Humans
  • Ketoprofen / therapeutic use
  • Magnesium / blood*
  • Male
  • Middle Aged
  • Sertraline / therapeutic use
  • Treatment Outcome


  • Antidepressive Agents
  • Ketoprofen
  • Magnesium
  • Sertraline
  • Calcium