Zinc in depression: From development to treatment: A comparative/ dose response meta-analysis of observational studies and randomized controlled trials

Highlights

• Highest level of zinc intake was associated with 28% reduced the risk of depression.

• zinc supplementation significantly lowered depressive symptom scores of depressed patients.

• our studies found the beneficial effect of zinc monotherapy versus adjunctive therapy.

Abstract

Background

A previous meta-analysis suggested that zinc status may be linked to depression status. However, it remains unclear whether zinc status can predict the risk of depression development, or whether the monotherapy of zinc is superior to the combination of zinc supplementation and antidepressant medications in the treatment of depression. Therefore, this meta-analysis aimed to clarify the impact of zinc status and supplementation on depression development and status across all available evidence.

Methods

PubMed, EMBASE, Scopus, and ISI web of science were searched, up to 14 May 2020, for relevant publications. Pooled relative risks (RRs) with 95% confidence intervals (CI) in observational studies, and mean and standard deviation (SD) for the change in depression score in RCTs were calculated using a random-effects model.

Results

The meta-analysis of RCTs indicated that zinc supplementation significantly lowered depressive symptom scores of depressed patients [weighted mean difference (WMD = −4.15 point; 95% CI: −6.56, −1.75 point; P < 0.01)], and the improvement in depression status occurred only when zinc supplementation was prescribed as a monotherapy. The cohort studies showed that the highest level of zinc intake was associated with a 28% reduced risk of depression (RR: 0.66; 95% CI: 0.50, 0.82; I² = 13.90). Dose-response analyses revealed a significant non-linear effect of baseline mood status on depression score.

Conclusion

Current evidence from observational studies and RCT's supports the potential benefits zinc to reduce the risk of, and alleviate, depression. However, further trials are needed to confirm the beneficial effect of zinc as a monotherapy versus adjunctive therapies.

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.