Hostname: page-component-7dd5485656-gs9qr Total loading time: 0 Render date: 2025-10-22T07:53:21.830Z Has data issue: false hasContentIssue false
  • English
  • Français

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

Published online by Cambridge University Press:  27 May 2021

Rana Fadhil Mousa ,
Hasan Najah Smesam ,
Hasan Abbas Qazmooz ,
Hussein Kadhem Al-Hakeim  and
Michael Maes Open the ORCID record for Michael Maes [Opens in a new window]
Rana Fadhil Mousa
Affiliation:
Faculty of Veterinary Medicine, University of Kerbala, Karbala, Iraq
Hasan Najah Smesam
Affiliation:
Department of Chemistry, College of Science, University of Kufa, Najaf, Iraq
Hasan Abbas Qazmooz
Affiliation:
Department of Ecology, College of Science, University of Kufa, Najaf, Iraq
Hussein Kadhem Al-Hakeim
Affiliation:
Department of Chemistry, College of Science, University of Kufa, Najaf, Iraq
Michael Maes*
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria School of Medicine, IMPACT Strategic Research Centre, Deakin University, Geelong, Victoria, Australia
*
*Author for correspondence: Prof. Dr. Michael Maes, MD, PhD Email: dr.michaelmaes@hotmail.com
Get access Rights & Permissions [Opens in a new window]

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.

Keywords

Unstable anginainflammationneuro-immunemajor depressionoxidative stressatherogenicity

Information

Type
Original Research
Information
CNS Spectrums , Volume 27 , Issue 6 , December 2022 , pp. 676 - 690
Copyright
© The Author(s), 2021. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Rahman, MS, Woollard, K. Atherosclerosis. Adv Exp Med Biol. 2017;1003:121–144. doi:10.1007/978-3-319-57613-8_7.CrossRefGoogle ScholarPubMed
Mc Namara, K, Alzubaidi, H, Jackson, JK. Cardiovascular disease as a leading cause of death: how are pharmacists getting involved? Integr Pharm Res Pract. 2019;8:1–11. doi:10.2147/IPRP.S133088.CrossRefGoogle ScholarPubMed
Wiviott, SD, Braunwald, E. Unstable angina and non-ST-segment elevation myocardial infarction: part I. Initial evaluation and management, and hospital care. Am Fam Physician. 2004;70(3):525–532.Google ScholarPubMed
Strik, JJ, Honig, A, Maes, M. Depression and myocardial infarction: relationship between heart and mind. Prog Neuropsychopharmacol Biol Psychiatry. 2001;25(4):879–892.CrossRefGoogle ScholarPubMed
Maes, M, Ruckoanich, P, Chang, YS, et al. Multiple aberrations in shared inflammatory and oxidative & nitrosative stress (IO&NS) pathways explain the co-association of depression and cardiovascular disorder (CVD), and the increased risk for CVD and due mortality in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(3):769–783. doi:10.1016/j.pnpbp.2010.06.008.CrossRefGoogle ScholarPubMed
de Melo, LGP, Nunes, SOV, Anderson, G, et al. Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:34–50.CrossRefGoogle ScholarPubMed
Hare, DL, Toukhsati, SR, Johansson, P, et al. Depression and cardiovascular disease: a clinical review. Eur Heart J. 2014;35(21):1365–1372.CrossRefGoogle ScholarPubMed
Moise, N, Khodneva, Y, Richman, J, et al. Elucidating the association between depressive symptoms, coronary heart disease, and stroke in black and white adults: the reasons for geographic and racial differences in stroke (REGARDS) study. J Am Heart Assoc. 2016;5(8). doi:10.1161/jaha.116.003767.CrossRefGoogle ScholarPubMed
Raič, M. Depression and heart diseases: leading health problems. Psychiatr Danub. 2017;29(suppl 4):770–777.Google ScholarPubMed
Lespérance, F, Frasure-Smith, N, Juneau, M, et al. Depression and 1-year prognosis in unstable angina. Arch Intern Med. 2000;160(9):1354–1360.CrossRefGoogle ScholarPubMed
Hansson, G, Hermansson, A. The immune system in atherosclerosis. Nat Immunol. 2011;12:204–212.CrossRefGoogle ScholarPubMed
Li, B, Li, W, Li, X, et al. Inflammation: a novel therapeutic target/direction in atherosclerosis. Curr Pharm Des. 2017;23(8):1216–1227. doi:10.2174/1381612822666161230142931.CrossRefGoogle ScholarPubMed
Leopold, JA, Loscalzo, J. Oxidative risk for atherothrombotic cardiovascular disease. Free Radic Biol Med. 2009;47(12):1673–1706. doi:10.1016/j.freeradbiomed.2009.09.009.CrossRefGoogle ScholarPubMed
Sinha, K, Das, J, Pal, PB, et al. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol. 2013;87(7):1157–1180. doi:10.1007/s00204-013-1034-4.CrossRefGoogle ScholarPubMed
McMurray, J, Ray, S, Abdullah, I, et al. Plasma endothelin in chronic heart failure. Circulation. 1992;85(4):1374–1379.CrossRefGoogle ScholarPubMed
Maes, M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry. 1995;19(1):11–38.CrossRefGoogle ScholarPubMed
Vargas, HO, Nunes, SOV, Barbosa, DS, et al. Castelli risk indexes 1 and 2 are higher in major depression but other characteristics of the metabolic syndrome are not specific to mood disorders. Life Sci. 2014;102(1):65–71.CrossRefGoogle Scholar
Bortolasci, CC, Vargas, HO, Nunes, SOV, et al. Factors influencing insulin resistance in relation to atherogenicity in mood disorders, the metabolic syndrome and tobacco use disorder. J Affect Disord. 2015;179:148–155.CrossRefGoogle ScholarPubMed
Nunes, SOV, de Melo, LGP, de Castro, MRP, et al. Atherogenic index of plasma and atherogenic coefficient are increased in major depression and bipolar disorder, especially when comorbid with tobacco use disorder. J Affect Disord. 2015;172:55–62.CrossRefGoogle ScholarPubMed
Oliveira, SR, Kallaur, AP, Lopes, J, et al. Insulin resistance, atherogenicity, and iron metabolism in multiple sclerosis with and without depression: associations with inflammatory and oxidative stress biomarkers and uric acid. Psychiatry Res. 2017;250:113–120. doi:10.1016/j.psychres.2016.12.039.CrossRefGoogle ScholarPubMed
Silva, N, Atlantis, E, Ismail, K. A review of the association between depression and insulin resistance: pitfalls of secondary analyses or a promising new approach to prevention of type 2 diabetes? Curr Psychiatry Reports. 2012;14(1):8–14.10.1007/s11920-011-0245-8CrossRefGoogle ScholarPubMed
Kan, C, Silva, N, Golden, SH, et al. A systematic review and meta-analysis of the association between depression and insulin resistance. Diabetes Care. 2013;36(2):480–489.CrossRefGoogle ScholarPubMed
Landucci Bonifácio, K, Sabbatini Barbosa, D, Gastaldello Moreira, E, et al. Indices of insulin resistance and glucotoxicity are not associated with bipolar disorder or major depressive disorder, but are differently associated with inflammatory, oxidative and nitrosative biomarkers. J Affect Disord. 2017;222:185–194. doi:10.1016/j.jad.2017.07.010.CrossRefGoogle ScholarPubMed
Qazmooz, HA, Smeism, HN, Mousa, RF, et al. Trace element, immune and opioid biomarkers of unstable angina, increased atherogenicity and insulin resistance: results of machine learning. J Trace Elem Med Biol. 2020;64:126703. CrossRefGoogle ScholarPubMed
Mallat, Z, Besnard, S, Duriez, M, et al. Protective role of interleukin-10 in atherosclerosis. Circ Res. 1999;85(8):e17–e24.CrossRefGoogle ScholarPubMed
Maes, M, Carvalho, AF. The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol. 2018;55(12):8885–8903.CrossRefGoogle ScholarPubMed
Trujillo, J, Vieira, MC, Lepsch, J, et al. A systematic review of the associations between maternal nutritional biomarkers and depression and/or anxiety during pregnancy and postpartum. J Affect Disord. 2018;232:185–203.CrossRefGoogle ScholarPubMed
Sotoudeh, G, Raisi, F, Amini, M, et al. Vitamin D deficiency mediates the relationship between dietary patterns and depression: a case–control study. Annals Gen Psychiatry. 2020;19:1–8.10.1186/s12991-020-00288-1CrossRefGoogle ScholarPubMed
Vellekkatt, F, Menon, V. Efficacy of vitamin D supplementation in major depression: a meta-analysis of randomized controlled trials. J Post Med. 2019;65(2):74 Google ScholarPubMed
Al-Fadhel, SZ, Al-Hakeim, HK, Al-Dujaili, AH, et al. IL-10 is associated with increased mu-opioid receptor levels in major depressive disorder. Eur Psychiatry. Apr. 2019;57:46–51. doi:10.1016/j.eurpsy.2018.10.001.CrossRefGoogle ScholarPubMed
Browne, CA, Lucki, I. Targeting opioid dysregulation in depression for the development of novel therapeutics. Pharmacol Ther. 2019;201:51–76. doi:10.1016/j.pharmthera.2019.04.009.CrossRefGoogle ScholarPubMed
Callaghan, CK, Rouine, J, O’Mara, SM. Potential roles for opioid receptors in motivation and major depressive disorder. Prog Brain Res. 2018;239:89–119. doi:10.1016/bs.pbr.2018.07.009.CrossRefGoogle ScholarPubMed
Ni, M, You, Y, Chen, J, et al. Copper in depressive disorder: a systematic review and meta-analysis of observational studies. Psychiatry Res. 2018;267:506–515.CrossRefGoogle ScholarPubMed
Anderson, J, Adams, C, Antman, E, et al. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(23):e663–e828.Google Scholar
Campeau, L. Letter: grading of angina pectoris. Circulation. 1976;54(3):522–523.CrossRefGoogle ScholarPubMed
Mancia, G, Fagard, R, Narkiewicz, K, et al. ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Press. 2013, 2013;22(4):193–278.CrossRefGoogle Scholar
WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: report of a WHO/IDF consultation; 2006.Google Scholar
WHO. Use of glycated haemoglobin (HbA1c) in diagnosis of diabetes mellitus: abbreviated report of a WHO consultation; 2011.Google Scholar
American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5™(5th ed.), 2013, American Psychiatric Publishing, Inc., Washington, DC, USA. https://doi.org/10.1176/appi.books.9780890425596.Google Scholar
Beck, AT, Steer, RA, Ball, R, et al. Comparison of Beck Depression Inventories-IA and-II in psychiatric outpatients. J Pers Assess. 1996;67(3):588–597.CrossRefGoogle ScholarPubMed
Wang, Y-P, Gorenstein, C. Psychometric properties of the Beck Depression Inventory-II: a comprehensive review. Braz J Psychiatry. 2013;35(4):416–431.CrossRefGoogle ScholarPubMed
Flauzino, T, Pereira, WLdCJ, Alfieri, DF, et al. Disability in multiple sclerosis is associated with age and inflammatory, metabolic and oxidative/nitrosative stress biomarkers: results of multivariate and machine learning procedures. Metab Brain Dis. 2019;34(5):1401–1413.CrossRefGoogle ScholarPubMed
Bonifácio, KL, Barbosa, DS, Moreira, EG, et al. Increased nitro-oxidative stress toxicity as a major determinant of increased blood pressure in mood disorders. J Affect Disord. 2021;278:226–238.CrossRefGoogle Scholar
Benjamini, Y, Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57(1):289–300.Google Scholar
Ringle, C, Da Silva, D, Bido, D. Structural equation modeling with the SmartPLS. Braz J Market. 2015;13(2). https://ssrn.com/abstract=2676422.Google Scholar
Whang, W, Shimbo, D, Kronish, IM, et al. Depressive symptoms and all-cause mortality in unstable angina pectoris (from the Coronary Psychosocial Evaluation Studies [COPES]). Am J Cardiol. 2010;106(8):1104–1107.CrossRefGoogle ScholarPubMed
Lichtman, JH, Froelicher, ES, Blumenthal, JA, et al. Depression as a risk factor for poor prognosis among patients with acute coronary syndrome: systematic review and recommendations: a scientific statement from the American Heart Association. Circulation. 2014;129(12):1350–1369.CrossRefGoogle ScholarPubMed
Katon, W, Lin, EH, Kroenke, K. The association of depression and anxiety with medical symptom burden in patients with chronic medical illness. Gen Hosp Psychiatry. 2007;29(2):147–155.10.1016/j.genhosppsych.2006.11.005CrossRefGoogle ScholarPubMed
Liang, Y, Yan, Z, Cai, C, et al. Association between lipid profile and depressive symptoms among Chinese older people: mediation by cardiovascular diseases? Int J Behav Med. 2014;21(4):590–596.CrossRefGoogle ScholarPubMed
Maes, M, Smith, R, Christophe, A, et al. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers. Acta Psychiatr Scand. 1997;95(3):212–221.CrossRefGoogle ScholarPubMed
Moreira, EG, Boll, KM, Correia, DG, et al. Why should psychiatrists and neuroscientists worry about paraoxonase 1? Curr Neuropharmacol. 2019;17(11):1004–1020.CrossRefGoogle ScholarPubMed
Moreira, EG, Correia, DG, Bonifácio, KL, et al. Lowered PON1 activities are strongly associated with depression and bipolar disorder, recurrence of (hypo) mania and depression, increased disability and lowered quality of life. World J Biol Psychiatry. 2019;20(5):368–380.CrossRefGoogle ScholarPubMed
Maes, M, Sirivichayakul, S, Matsumoto, AK, et al. Increased levels of plasma tumor necrosis factor-α mediate schizophrenia symptom dimensions and neurocognitive impairments and are inversely associated with natural IgM directed to malondialdehyde and paraoxonase 1 activity. Mol Neurobiol. 2020;57(5):2333–2345.CrossRefGoogle ScholarPubMed
Billecke, S, Draganov, D, Counsell, R, et al. Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab Dispos. 2000;28(11):1335–1342.Google Scholar
Mackness, MI, Mackness, B, Durrington, PN. Paraoxonase and coronary heart disease. Atheroscler Suppl. 2002;3(4):49–55.CrossRefGoogle ScholarPubMed
Costa, LG, Cole, TB, Furlong, CE. Paraoxonase (PON1): from toxicology to cardiovascular medicine. Acta Biomed. 2005;76(suppl 2):50–57.Google ScholarPubMed
Kowalska, K, Socha, E, Milnerowicz, H. Review: the role of paraoxonase in cardiovascular diseases. Ann Clin Lab Sci. 2015;45(2):226–233.Google ScholarPubMed
Chistiakov, DA, Melnichenko, AA, Orekhov, AN, et al. Paraoxonase and atherosclerosis-related cardiovascular diseases. Biochimie. 2017;132:19–27.CrossRefGoogle ScholarPubMed
Di Pino, A, DeFronzo, RA. Insulin resistance and atherosclerosis: implications for insulin-sensitizing agents. Endocr Rev. 2019;40(6):1447–1467. doi:10.1210/er.2018-00141.CrossRefGoogle ScholarPubMed
Wiener, CD, Moreira, FP, Portela, LV, et al. Interleukin-6 and Interleukin-10 in mood disorders: a population-based study. Psychiatry Res. 2019;273:685–689. doi:10.1016/j.psychres.2019.01.100.CrossRefGoogle ScholarPubMed
Caruso, G, Fresta, CG, Grasso, M, et al. Inflammation as the common biological link between depression and cardiovascular diseases: can carnosine exert a protective role? Curr Med Chem. 2020;27(11):1782–1800. doi:10.2174/0929867326666190712091515.CrossRefGoogle ScholarPubMed
Maes, M, Anderson, G, Kubera, M, et al. Targeting classical IL-6 signalling or IL-6 trans-signalling in depression? Expert Opin Ther Targets. 2014;18(5):495–512.CrossRefGoogle ScholarPubMed
Kallaur, AP, Lopes, J, Oliveira, SR, et al. Immune-inflammatory and oxidative and nitrosative stress biomarkers of depression symptoms in subjects with multiple sclerosis: increased peripheral inflammation but less acute neuroinflammation. Mol Neurobiol. 2016;53(8):5191–5202.CrossRefGoogle ScholarPubMed
Roomruangwong, C, Barbosa, DS, Matsumoto, AK, et al. Activated neuro-oxidative and neuro-nitrosative pathways at the end of term are associated with inflammation and physio-somatic and depression symptoms, while predicting outcome characteristics in mother and baby. J Affect Disord. 2017;223:49–58.10.1016/j.jad.2017.07.002CrossRefGoogle ScholarPubMed
Twayej, AJ, Al-Hakeim, HK, Al-Dujaili, AH, et al. Lowered zinc and copper levels in drug-naïve patients with major depression: Effects of antidepressants, ketoprofen and immune activation. World J Biol Psychiatry. 2020;21(2):127–138.CrossRefGoogle ScholarPubMed
Bao, B, Prasad, AS, Beck, FW, et al. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. Am J Clin Nutr. 2010;91(6):1634–1641.CrossRefGoogle ScholarPubMed
Sagarad, SV, Sukhani, N, Machanur, B, et al. Effect of vitamin D on anginal episodes in vitamin D deficient patients with chronic stable angina on medical management. J Clin Diagnos Res. 2016;10(8):OC24–OC26. doi:10.7860/JCDR/2016/20521.8345.Google ScholarPubMed
Ramadan, R, Vaccarino, V, Esteves, F, et al. Association of vitamin D status with mental stress induced myocardial ischemia in patients with coronary artery disease. Psychosom Med. 2014;76(7):569 CrossRefGoogle ScholarPubMed
Meredith, AJ, McManus, BM. Vitamin D in heart failure. J Card Fail. 2013;19(10):692–711. doi:10.1016/j.cardfail.2013.09.002.CrossRefGoogle ScholarPubMed
Huang, J, Wang, Z, Hu, Z, et al. Association between blood vitamin D and myocardial infarction: a meta-analysis including observational studies. Clin Chim Acta. 2017;471:270–275. doi:10.1016/j.cca.2017.06.018.CrossRefGoogle ScholarPubMed
Jhee, JH, Kim, H, Park, S, et al. Vitamin D deficiency is significantly associated with depression in patients with chronic kidney disease. PLoS One. 2017;12(2):e0171009 CrossRefGoogle ScholarPubMed
Barbonetti, A, Cavallo, F, D’Andrea, S, et al. Lower vitamin D levels are associated with depression in people with chronic spinal cord injury. Arch Phys Med Rehab. 2017;98(5):940–946.CrossRefGoogle ScholarPubMed
Jamall, OA, Feeney, C, Zaw-Linn, J, et al. Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury. Clin Endocrinol. 2016;85(4):636–644.CrossRefGoogle ScholarPubMed
Casseb, GA, Ambrósio, G, Rodrigues, ALS, et al. Levels of 25-hydroxyvitamin D3, biochemical parameters and symptoms of depression and anxiety in healthy individuals. Metabol Brain Dis. 2019;34(2):527–535.10.1007/s11011-018-0371-7CrossRefGoogle ScholarPubMed
Kieboom, BC, Licher, S, Wolters, FJ, et al. Serum magnesium is associated with the risk of dementia. Neurology. 2017;89(16):1716–1722.CrossRefGoogle ScholarPubMed
Zhang, W, Iso, H, Ohira, T, et al. Associations of dietary magnesium intake with mortality from cardiovascular disease: the JACC study. Atherosclerosis. 2012;221(2):587–595.CrossRefGoogle ScholarPubMed
Kostov, K, Halacheva, L. Role of magnesium deficiency in promoting atherosclerosis, endothelial dysfunction, and arterial stiffening as risk factors for hypertension. Int J Mol Sci. 2018;19(6):1724 CrossRefGoogle ScholarPubMed
You, S, Zhong, C, Du, H, et al. Admission low magnesium level is associated with in-hospital mortality in acute ischemic stroke patients. Cerebrovasc Dis. 2017;44(1–2):35–42.CrossRefGoogle ScholarPubMed
Al-Dujaili, AH, Al-Hakeim, HK, Twayej, AJ, et al. Total and ionized calcium and magnesium are significantly lowered in drug-naïve depressed patients: effects of antidepressants and associations with immune activation. Metabolic Brain Dis. 2019;34(5):1493–1503.CrossRefGoogle ScholarPubMed
Qu, X, Jin, F, Hao, Y, et al. Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies. PLoS One. 2013;8(3):e57720 CrossRefGoogle ScholarPubMed
Gueux, E, Azais-Braesco, V, Bussiére, L, et al. Effect of magnesium deficiency on triacylglycerol-rich lipoprotein and tissue susceptibility to peroxidation in relation to vitamin E content. Br J Nutr. 1995;74(6):849–856. doi:10.1079/BJN19950011.Google ScholarPubMed
Barbagallo, M, Dominguez, LJ, Galioto, A, et al. Role of magnesium in insulin action, diabetes and cardio-metabolic syndrome X. Mol Aspects Med. 2003;24(1–3):39–52.CrossRefGoogle ScholarPubMed
Belin, RJ, He, K. Magnesium physiology and pathogenic mechanisms that contribute to the development of the metabolic syndrome. Magnes Res. 2007;20(2):107–129.Google Scholar
Al-Hakeim, HK, Zeki Al-Fadhel, S, Maes, M. In major depression, increased kappa and mu opioid receptor levels are associated with immune activation. Acta Neuropsychiatr. 2020;32(2):99–108. doi:10.1017/neu.2019.47.CrossRefGoogle ScholarPubMed
Wilbert-Lampen, U, Trapp, A, Barth, S, et al. Effects of beta-endorphin on endothelial/monocytic endothelin-1 and nitric oxide release mediated by mu1-opioid receptors: a potential link between stress and endothelial dysfunction? Endothelium. 2007;14(2):65–71. doi:10.1080/10623320701346585.CrossRefGoogle ScholarPubMed
Okano, T, Sato, K, Shirai, R, et al. β-endorphin mediates the development and instability of atherosclerotic plaques. Int J Endocrinol. 2020;2020:4139093. doi:10.1155/2020/4139093.CrossRefGoogle ScholarPubMed
Moustafa, SR, Al-Rawi, KF, Stoyanov, D, et al. The endogenous opioid system in schizophrenia and treatment resistant schizophrenia: increased plasma endomorphin 2, and κ and μ opioid receptors are associated with interleukin-6. Diagnostics (Basel). 2020;10(9):633. doi:10.3390/diagnostics10090633.CrossRefGoogle ScholarPubMed
Narang, RL, Gupta, KR, Narang, AP, et al. Levels of copper and zinc in depression. Ind J Physiol Pharmacol. 1991;35(4):272–274.Google ScholarPubMed
Styczeń, K, Sowa-Kućma, M, Siwek, M, et al. Study of the serum copper levels in patients with major depressive disorder. Biol Trace Elem Res. 2016;174(2):287–293. doi:10.1007/s12011-016-0720-5.CrossRefGoogle ScholarPubMed
Levine, J, Stein, D, Rapoport, A, et al. High serum and cerebrospinal fluid Ca/Mg ratio in recently hospitalized acutely depressed patients. Neuropsychobiol. 1999;39(2):63–70. doi:10.1159/000026562.CrossRefGoogle ScholarPubMed
Małecki, R, Adamiec, R. [The role of calcium ions in the pathomechanism of the artery calcification accompanying atherosclerosis]. Postepy Hig Med Dosw (Online). 2005;59:42–47. Rola jonów wapnia w patomechanizmie zwapnień tetnic towarzyszacych miazdzycy.Google ScholarPubMed
Kalampogias, A, Siasos, G, Oikonomou, E, et al. Basic mechanisms in atherosclerosis: the role of calcium. Med Chem. 2016;12(2):103–113. doi:10.2174/1573406411666150928111446.CrossRefGoogle ScholarPubMed
Glassman, AH, Bigger, JT, Gaffney, M. Psychiatric characteristics associated with long-term mortality among 361 patients having an acute coronary syndrome and major depression: seven-year follow-up of SADHART participants. Arch Gen Psychiatry. 2009;66(9):1022–1029.CrossRefGoogle ScholarPubMed
Stoyanov, DS. The endophenotype project and the validation theory: integration of neurobiology and psychiatry. Folia Medica LII. 2010;1:18–24.Google Scholar
Stoyanov, D, Maes, MH. How to construct neuroscience-informed psychiatric classification? Towards nomothetic networks psychiatry. World J Psychiatry. 2021;11(1):1–12. doi:10.5498/wjp.v11.i1.1.CrossRefGoogle ScholarPubMed
Maes, M, Moraes, JB, Bonifacio, KL, et al. Towards a new model and classification of mood disorders based on risk resilience, neuro-affective toxicity, staging, and phenome features using the nomothetic network psychiatry approach. Metab Brain Dis. 2021;36(3):509–521. doi:10.1007/s11011-020-00656-6.CrossRefGoogle ScholarPubMed
Maes, M, Vojdani, A, Galecki, P, et al. How to construct a bottom-up nomothetic network model and disclose novel nosological classes by integrating risk resilience and adverse outcome pathways with the phenome of schizophrenia. Brain Sci. 2020;10(9):645. doi:10.3390/brainsci10090645.CrossRefGoogle ScholarPubMed