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

  • Arafat Hussein Al-Dujaili
  • Hussein Kadhem Al-Hakeim
  • Ahmed Jasim Twayej
  • Michael MaesEmail author
Original Article


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


Depression Cytokines Inflammation Indoleamine 2,3-dioxygenase Neuro-immune 



Analysis of variance


Beck Depression Inventory-II


Body mass index




Compensatory immune regulatory system




C-reactive protein


Coefficient of variation


Enzyme-linked immunosorbent assay


Generalized estimating equation


General linear model


Horseradish peroxidase




10th revision of the International Statistical Classification of Diseases and Related Health Problems


Indoleamine 2,3-dioxygenase






Immune response system


Macrophage type 1


Major depressive disorder




Non-steroidal anti-inflammatory drugs




Transforming growth factor-beta1


T helper-




Tregulatory cells



We would like to thank the staff of the Asia Clinical Laboratory in Najaf city for their help in the ELISA measurements. We greatly appreciate the continuous cooperation of the staff of the Psychiatry Unit at Al-Hakeem General Hospital.

Author’s contributions

All the contributing authors have participated in the preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest with any commercial or other association in connection with the submitted article.


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Authors and Affiliations

  1. 1.Faculty of MedicineUniversity of KufaKufaIraq
  2. 2.Department of Chemistry, College of ScienceUniversity of KufaKufaIraq
  3. 3.Pathological Analysis Department, College of Health and MedicalAl-Kafeel UniversityNajafIraq
  4. 4.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  5. 5.Department of PsychiatryMedical University of PlovdivPlovdivBulgaria
  6. 6.School of Medicine, IMPACT Strategic Research CentreDeakin UniversityGeelongAustralia
  7. 7.IMPACT Strategic Research Center, Barwon HealthDeakin UniversityGeelongAustralia

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