Review articleZinc in depression: From development to treatment: A comparative/ dose response meta-analysis of observational studies and randomized controlled trials
Introduction
The monoamine hypothesis, accepted as the most common hypothesis with regard to the pathophysiology of depression [1,2], has led to the development of almost all currently used antidepressant drugs [3], including selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) [3,4]. However, remission is achieved in only one-third of patients after treatment with SSRIs [3]. Antidepressants have latency of response [1,5], indeed, some evidence suggests that the monoamine hypothesis may be inadequate and emphasizes the need for creating alternative, preventative and treatment, approaches to antidepressant medication [1,4]. Micronutrients currently represent the most prominent and valid alternate to monoamine-based antidepressant medicine, as introduced in the “nutritional psychiatry hypothesis” [6,7].
Zinc is a micronutrient to have received much attention, due to its' possible role in depression [8]; for instance, zinc dysregulation in the hippocampus, amygdala, and the cerebral cortex is purportedly linked to the pathophysiology of depression [[9], [10], [11], [12], [13]]. Furthermore, dysregulation of brain zinc status is reported in many psychiatric and neurological disorders, such as schizophrenia [14], mood disorders [15], Parkinson's [16], and Alzheimer's disease [16]. Regulation of zinc levels within the brain may have a critical therapeutic role in neuropsychiatric diseases [11]. Indeed, support for this hypothesis originates from studies' reporting that zinc deprivation can induce depressive-like behavior, which can be effectively reversed by zinc supplementation [17,18]. Furthermore, it is conceivable that zinc could be used to enhance the antidepressant effects of drugs belonging to the SSRI group [19,20]. Considering this viewpoint, a connection between zinc and depression is highly probable. Concordantly, a meta-analysis of seventeen observational studies reported that serum zinc concentration was lower in depressive patients, as compared to a healthy population, whilst the severity of depression status was related to the degree of zinc deficiency [21]. A recent meta-analysis, by Li et al., reported an inverse association between zinc status and risk of depression; however, this study exclusively considered zinc intake [22]. Several meta-analyses have investigated the effect of zinc supplementation on depression status, however, these studies mainly focused on the efficacy adjunctive zinc therapy [[23], [24], [25]]. Notwithstanding the previous investigations, it is unclear whether the monotherapy of zinc is superior to the combination of zinc supplementation and antidepressant medications in depression, furthermore sources of heterogeneity are currently unclear. Therefore, this meta-analysis sought to clarify the impact of zinc status and supplementation on depression development and status across all available observational and RCTs, and to conduct a dose-response analysis to investigate whether the effect of zinc supplementation on depression symptoms had non-linear association.
Section snippets
Materials and methods
The present systematic review and meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [26]. We also followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines for reporting the meta-analysis of observational studies [27]. The review protocol was registered with the Prospero International Prospective Register of Systematic Reviews (http://www.crd. york.ac.uk/PROSPERO registration number
Literature search and study characteristics
A total of thirteen observational studies (9 cross-sectional studies and four cohort studies) [[38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49]], and eight RCTs [19,20,30,31,[50], [51], [52], [53]] met the inclusion criteria for meta-analysis, from the 4245 articles initially retrieved from the electronic search. The selection process of included studies is detailed in Supplementary Figs. 1 and 2.
RCT studies
RCT studies were conducted between 2003 and 2018 [19,20,30,31,[50], [51], [52]
Discussion
The present systematic review and meta-analysis of observational and RCTs studies sought to explicate the impact of zinc status and supplementation on depression development and treatment. First, our meta-analysis of cross-sectional studies revealed that inadequate zinc status (a combination of dietary zinc and serum zinc concentration) is prevalent among depressed patients. Second, we found that the highest level of zinc intake was associated with a 28% reduced risk of depression in the
Acknowledgments
The project was financially supported by the Larestan University of Medical Sciences, Research committee (IR.LARUMS.REC.1398.003).
References (63)
[43] Metallothioneins and other zinc-binding proteins in brain
Methods Enzymol
(1991)Neurobiology of zinc and zinc-containing neurons
Int Rev Neurobiol
(1989)- et al.
Brain, aging and neurodegeneration: role of zinc ion availability
Prog Neurobiol
(2005) - et al.
Time course of zinc deprivation-induced alterations of mice behavior in the forced swim test
Pharmacol Rep
(2012) - et al.
Zinc deficiency induces behavioral alterations in the tail suspension test in mice. Effect of antidepressants
Pharmacol Rep
(2012) - et al.
Zinc in depression: a meta-analysis
Biol Psychiatry
(2013) - et al.
Dietary zinc and iron intake and risk of depression: a meta-analysis
Psychiatry Res
(2017) - et al.
Efficacy of adding nutritional supplements in unipolar depression: a systematic review and meta-analysis
Eur Neuropsychopharmacol
(2017) - et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986) - et al.
Relationship of zinc status with depression and anxiety among elderly population
Clinical Nutrition ESPEN
(2020)
Nutrient intakes and the common mental disorders in women
J Affect Disord
Dietary zinc intake and the risk of depression in middle-aged men: a 20-year prospective follow-up study
J Affect Disord
Association of total zinc, iron, copper and selenium intakes with depression in the US adults
J Affect Disord
Low dietary or supplemental zinc is associated with depression symptoms among women, but not men, in a population-based epidemiological survey
J Affect Disord
Dietary intake of minerals in relation to depressive symptoms in Japanese employees: the Furukawa Nutrition and Health Study
Nutrition
Dietary zinc is associated with a lower incidence of depression: findings from two Australian cohorts
J Affect Disord
Zinc sulphate: a reasonable choice for depression management in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial
Pharmacol Rep
Zinc supplementation augments efficacy of imipramine in treatment resistant patients: a double blind, placebo-controlled study
J Affect Disord
Zinc deficiency impairs neuronal precursor cell proliferation and induces apoptosis via p53-mediated mechanisms
Brain Res
Zinc at glutamatergic synapses
Neuroscience
Involvement of NMDA receptors and L-arginine-nitric oxide pathway in the antidepressant-like effects of zinc in mice
Behav Brain Res
Neural basis of major depressive disorder: beyond monoamine hypothesis
Psychiatry Clin Neurosci
History and evolution of the monoamine hypothesis of depression
J Clin Psychiatry
Evaluation of outcomes with citalopram for depression using measurement-based care in STAR* D: implications for clinical practice
Am J Psychiatry
Zinc in the monoaminergic theory of depression: its relationship to neural plasticity
Neural Plast
Cellular and molecular mechanisms in the long-term action of antidepressants
Dialogues Clin Neurosci
Nutritional psychiatry research: an emerging discipline and its intersection with global urbanization, environmental challenges and the evolutionary mismatch
J Physiol Anthropol
Nutritional supplements in depressive disorders
Actas Esp Psiquiatr
Zinc homeostasis and neurodegenerative disorders
Front Aging Neurosci
Brain-delivery of zinc-ions as potential treatment for neurological diseases: mini review
Drug Deliv Lett
Über den topochemischen Nachweis von Zink im Ammonshorn verschiedener Säugetiere
Naturwissenschaften
Cited by (19)
Celiac disease and depressive disorders as nutritional implications related to common factors – A comprehensive review
2024, Behavioural Brain ResearchAssociation between serum zinc levels and suicidal ideation in US adults: A population-based cross-sectional study
2023, Journal of Affective DisordersNutrition and depressive disorders
2022, Pratiques en NutritionDietary zinc supplements: beneficial health effects and application in food, medicine and animals
2024, Journal of the Science of Food and Agriculture