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A pathway phenotype linking metabolic, immune, oxidative, and opioid pathways with comorbid depression, atherosclerosis, and unstable angina

Rana Fadhil Mousa1, Hasan Najah Smesam2, Hasan Abbas Qazmooz3,
Hussein Kadhem Al-Hakeim4 and Michael Maes5,6,7*
1Faculty of Veterinary Medicine, University of Kerbala, Karbala, Iraq, 2Department of Chemistry, College of Science,
University of Kufa, Najaf, Iraq, 3Department of Ecology, College of Science, University of Kufa, Najaf, Iraq, 4Department
of Chemistry, College of Science, University of Kufa, Najaf, Iraq, 5Department of Psychiatry, Faculty of Medicine,
Chulalongkorn University, Bangkok, Thailand, 6Department of Psychiatry, Medical University of Plovdiv, Plovdiv,
Bulgaria, and 7School of Medicine, IMPACT Strategic Research Centre, Deakin University, Geelong, Victoria, Australia
Abstract
Background. There is strong comorbidity between atherosclerosis (ATS) and depression which
is attributed to increased atherogenicity, insulin resistance (IR), and immune and oxidative
stress.
Aim of the study. To examine the role of the above pathways and mu-opioid receptor (MOR),
β-endorphin levels, zinc, copper, vitamin D3, calcium, and magnesium in depression due to
ATS/unstable angina (UA).
Methods. Biomarkers were assayed in 58 controls and 120 ATS patients divided into those with
moderate and severe depression according to the Beck Depression Inventory-II (BDI-II) scores
>19 and >29, respectively.
Results. Neural network and logistic regression models showed that severe depression due to
ATS/UA was best predicted by interleukin-6 (IL-6), UA, MOR, zinc, β-endorphin, calcium and
magnesium, and that moderate depression was associated with IL-6, zinc, MOR, β-endorphin,
UA, atherogenicity, IR, and calcium. Neural networks yielded a significant discrimination of
severe and moderate depression with an area under the receiver operating curves of 0.831 and
0.931, respectively. Using Partial Least Squares path analysis, we found that 66.2% of the
variance in a latent vector extracted from ATS/UA clinical features, and the BDI-II scores,
atherogenicity, and IR could be explained by the regression on IL-6, IL-10, zinc, copper, calcium,
MOR, and age. The BDI-II scores increased from controls to ATS to UA class III to UA class IV.
Conclusions. Immune activation, the endogenous opioid system, antioxidants, trace elements,
and macrominerals modulate a common core shared by increased depressive symptoms, ATS,
UA, atherogenicity, and IR.

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