Zinc as an inhibitor of NMDA receptor can exhibit antidepressant effect

  • Novi Dewi Tanjung Faculty of Medicine, Universitas Indonesia
  • Ninik Mudjihartini Faculty of Medicine, Universitas Indonesia
Keywords: zinc, antidepressant, depression, NMDA


Background : New antidepressant strategies are needed, due to unsatisfactory clinical efficacy and many side effects of commonly used drugs. Recent studies linking the pathophysiology of depression with glutamatergic imbalance. There is hyperactivity of the main excitatory system (glutamatergic) to its inhibition (GABAergic). N-methyl D-aspartate (NMDA) receptors as a part of glutamatergic synapses are potential targets for intervention. Antagonist administration for glutamatergic systems, such as zinc, can exhibit antidepressant effects. Objective : To observe the effect of zinc administration on NMDA receptors in depressed subjects Methods : In this paper, we provide a literature review. The method to achieve the objective consists of using literature exploration, which was conducted from February to June 2022 by searching the relevant studies from several databases. Results : Study trials both in human and animal subjects reveal that depression is associated with a lower concentration of zinc. Comparison between the lowest zinc intake with the highest zinc intake had significantly lower incidence of developing depression. Dietary zinc deficiency induces depression along with upregulation of the NMDA receptor complexes. Zinc’s antidepressant effects might be mediated through its action reducing NMDA channel-opening frequency. Conclusions : The presence of zinc may downregulate the glutamate response in binding to NMDA receptors. Because of numerous studies about the connection between zinc and depression, it seems that zinc may have the potency to develop new antidepressants. Since the capability of zinc administration to reduce depressive symptoms, it is expected leading to increased medication adherence, lower costs and better outcomes.


Download data is not yet available.

Author Biographies

Novi Dewi Tanjung, Faculty of Medicine, Universitas Indonesia
Master Program in Biomedical Sciences
Ninik Mudjihartini, Faculty of Medicine, Universitas Indonesia
Department of Biochemistry and Molecular Biology


Institute of Health Metrics and Evaluation. Global health data exchange [Internet]. 2021. Available from: http://ghdx.healthdata.org/gbd-results-tool?params=gbd-api-2019-permalink/d780dffbe8a381b25e1416884959e88b

World Health Organization. Depression overview [Internet]. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/depression

Sathyanarayana Rao TS, Asha MR, Ramesh BN, Jagannatha Rao KS. Understanding nutrition, depression and mental illnesses. Indian J Psychiatry 2008;50:77-82. doi: 10.4103/0019-5545.42391

Bonny Beardsley. Depression and nutrition [Internet]. 2009. Available from: http://www.healingwell.com/library/depression/beardsley1.asp

Shaheen Lakhan SE, Vieira KF. Nutritional therapies for mental disorders. Nutr Jr. 2008;7:2. doi: 10.1186/1475-2891-7-2

Nowak G, Szewczyk B, Pilc A. Zinc and depression. Pharmacological Reports 2005;57:713-18. doi: https://www.researchgate.net/publication/7389625

Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev. 1993;73:79–118. doi: 10.1152/physrev.1993.73.1.79

Szewczyk B. Zinc homeostasis and neurodegenerative disorders. Frontiers in Aging Neuroscience 2013;5. doi: 10.3389/fnagi.2013.00033

Mlyniec K and Nowak G. Zinc deficiency induces behavioral alterations in the tail suspension test in mice. Effect of antidepressants. Pharmacol. Rep. 2012;64:249–55. doi: 10.1016/s1734-1140(12)70762-4

Petrilli MA, Kranz TM, Kleinhaus K, Joe P, Getz M, Johnson P, et al. The emerging role for zinc in depression and psychosis. Frontiers in Pharmacology 2017;8. doi: 10.3389/fphar.2017.00414

Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS Neurol Disord Drug Targets 2007 Apr;6(2):101-15. doi: 10.2174/187152707780363267

Doboszewska U, Wlaź P, Nowak G, Radziwoń-Zaleska M, Cui R, Młyniec K. Zinc in the monoaminergic theory of depression: its relationship to neural plasticity. Neural Plast. 2017;2017:3682752. doi: 10.1155/2017/3682752

Swardfager W, Herrmann N, Mazereeuw G, Goldberger K, Harimoto T, Lanctôt KL. Zinc in depression: a meta-analysis. Biol Psychiatry. 2013 Dec 15;74(12):872-8. doi: 10.1016/j.biopsych.2013.05.008

Stanisławska M, Szkup-Jabłońska M, Jurczak A, Wieder-Huszla S, Samochowiec A, Jasiewicz A, et al. The severity of depressive symptoms vs. serum Mg and Zn levels in postmenopausal women. Biol Trace Elem Res. 2014 Jan;157(1):30-5. doi: 10.1007/s12011-013-9866-6

Vashum KP, McEvoy M, Milton AH, McElduff P, Hure A, Byles J, et al. Dietary zinc is associated with a lower incidence of depression: findings from two Australian cohorts. J. Affect. Disord. 2014;166:249–57. doi: 10.1016/j.jad.2014.05.016

Siwek M, Dudek D, Paul IA, Sowa-Ku ́cma M, Zi ̨eba A, Popik P, et al. Zinc supplementation augments efficacy of imipramine in treatment resistant patients: A double blind, placebo-controlled study. J. Affect. Disord. 2009;118:187–95. doi: 10.1016/j.jad.2009.02.014

Solati Z, Jazayeri S, Tehrani-Doost M, Mahmoodianfard S, and Gohari MR. Zinc monotherapy increases serum brain-derived neurotrophic factor (BDNF) levels and decreases depressive symptoms in overweight or obese subjects: a double-blind, randomized, placebo-controlled trial. Nutr. Neurosci. 2015;18: 162–168. doi: 10.1179/1476830513Y.0000000105

Doboszewska U, Szewczyk B, Sowa-Ku ́cma M, Młyniec K, Rafało A, Ostachowicz B, et al. Antidepressant activity of fluoxetine in the zinc deficiency model in rats involves the NMDA receptor complex. Behav. Brain Res. 2015;287: 323–30. doi: 10.1016/j.bbr.2015.03.064

Nowak G, Szewczyk B, Sadlik K, Piekoszewski W, Trela F, Florek E, et al. Reduced potency of zinc to interact with NMDA receptors in hippocampal tissue of suicide victims. Pol J Pharmacol. 2003 May-Jun;55(3):455-9.

Szewczyk B, Poleszak E, Sowa-Ku ́cma M, Wróbel A, Słotwi ́nski S, Listos J, et al. The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test. Amino Acids 2010;39: 205–17. doi: 10.1007/s00726-009-0412-y

Młyniec K. Zinc in the glutamatergic theory of depression. Current Neuropharmacology 2015;13:505-13. doi: 10.2174/1570159x13666150115220617

Tokita K, Yamaji T, and Hashimoto K. Roles of glutamate signaling in preclinical and/or mechanistic models of depression. Pharmacol. Biochem. Behav. 2012;100: 688–704. doi: 10.1016/j.pbb.2011.04.016

Nowak G. Does interaction between zinc and glutamate play a significant role in the mechanism of antidepressant action? Acta Pol. Pharm. 2001;8:73–75.

Prakash A, Bharti K, and Majeed AB. Zinc: indications in brain disorders. Fundam. Clin. Pharmacol. 2015;29:131–49. doi: 10.1111/fcp.12110

Ghasemi A, Zahediasl S, Hosseini-Esfahani F, Azizi F. Reference values for serum zinc concentration and prevalence of zinc deficiency in adult Iranian subjects. Biological trace element research. 2012;149: 307–14. doi: 10.1007/s12011-012-9445-2

Rabinovich D and Smadi Y [Internet]. 2022. Zinc. StatPearls Publishing LLC. available from: https://www.ncbi.nlm.nih.gov/books/NBK547698/

Muhamed PK, Vadstrup S. [Zinc is the most important trace element]. Ugeskr Laeger. 2014 Mar 3;176(5): V11120654.

Mocchegiani E, Bertoni-Freddari C, Marcellini F, Malavolta M. Brain, aging and neurodegeneration: Role of zinc ion availability. Prog. Neurobiol. 2005;75: 367–390. doi: 10.1016/j.pneurobio.2005.04.005

Grabrucker AM, Knight MJ, Proepper C, Bockmann J, Joubert M, Rowan M, et al. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J. 2011;30: 569–81. doi: 10.1038/emboj.2010.336

Tabata T, Ishida AT. A zinc-dependent Cl- current in neuronal somata. J. Neurosci. 1999;19: 5195–204. doi: 10.1523/JNEUROSCI.19-13-05195.1999

Weiss JH, Hartley DM, Koh JY, Choi DW. AMPA receptor activation potentiates zinc neurotoxicity. Neuron 1993;10: 43–9. doi: 10.1016/0896-6273(93)90240-r

Sowa-Ku ́cma M, Szewczyk B, Sadlik K, Piekoszewski W, Trela F, Opoka W, et al. Zinc, magnesium and NMDA receptor alterations in the hippocampus of suicide victims. J. Affect. Disord. 2013;151: 924–31. doi: 10.1016/j.jad.2013.08.009

Mathews DC, Henter ID, and Zarate CA. Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date. Drugs 2012;72: 1313–33. doi: 10.2165/11633130-000000000-00000

Szewczyk B, Poleszak E, Pilc A, Nowak G. Ionic glutamate modulators in depression (zinc, magnesium). P. Skolnick (ed.), Glutamate-based Therapies for Psychiatric Disorders, Milestones in Drug Therapy 2010:21-38. doi: 10.1007/978-3-0346-0241-9_2

Qi Z, Liu KJ. The interaction of zinc and the blood-brain barrier under physiological and ischemic conditions. Toxicology and Applied Pharmacology 2019;364:114–19. https://doi.org/10.1016/j.taap.2018.12.018

Marger L, Schubert CR, and Bertrand D. Zinc: an underappreciated modulatory factor of brain function. Biochem. Pharmacol. 2014;91: 426–35. doi: 10.1016/j.bcp.2014.08.002

Howland JG and Wang YT. Synaptic plasticity in learning and memory: stress effects in the hippocampus. Prog. Brain Res. 2008;169: 145–58. doi: 10.1016/S0079-6123(07)00008-8

Salari S, Khomand P, Arasteh M, Yousefzamani B, Hassanzadeh K. Zinc sulphate: a reasonable choice for depression management in patients with multiple sclerosis: a randomized, double blind, placebo controlled clinical trial. Pharmacol. Rep. 2015;67: 606–9. doi: 10.1016/j.pharep.2015.01.002

Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. The Psychiatric clinics of North America. 1996;19: 179–200. doi: 10.1016/s0193-953x(05)70283-5

McLoughlin IJ, Hodge JS. Zinc in Depressive Disorder. Acta psychiatrica Scandinavica. 1990;82: 451–53. doi: 10.1111/j.1600-0447.1990.tb03077.x

Ranjbar E, Kasaei MS, Mohammad-Shirazi M, Nasrollahzadeh J, Rashidkhani B, Shams J, et al. Effects of zinc supplementation in patients with major depression: a randomized clinical trial. Iran J Psychiatry. 2013 Jun; 8(2): 73–9.

Siwek M, Dudek D, Schlegel-Zawadzka M, Morawska A, Piekoszewski W, Opoka W, et al. Serum zinc level in depressed patients during zinc supplementation of imipramine treatment. Journal of affective disorders. 2010;126: 447–52. doi: 10.1016/j.jad.2010.04.024

da Silva LEM, de Santana MLP, Costa PRdF, Pereira EM, Nepomuceno CMM, Queiroz VAdO. Zinc supplementation combined with antidepressant drugs for treatment of patients with depression: a systematic review and meta-analysis. Nutrition Reviews 2020;Vol. 79(1): 1–12. doi: 10.1093/nutrit/nuaa039

Szewczyk B, Kubera M, Nowak G. The role of zinc in neurodegenerative inflammatory pathways in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35: 693–701. doi: 10.1016/j.pnpbp.2010.02.010

Walker AJ, Kim Y, Price JB, et al. Stress, inflammation, and cellular vulnerability during early stages of affective disorders: biomarker strategies and opportunities for prevention and intervention. Front Psychiatry. 2014;5: 34. doi: 10.3389/fpsyt.2014.00034

Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry. 2007;12: 988–1000. doi: 10.1038/sj.mp.4002006



Most read articles by the same author(s)