Protective role of antioxidant supplementation for depression and anxiety: A meta-analysis of randomized clinical trials

Depression is a mental disorder characterized by persistent sadness, retardation of thinking, decreased volitional activity, and cognitive impairment. In 2008, WHO ranked major depressive disorder the third cause of burden of disease worldwide and projected that the disease will rank first by 2030. Globally, the 12-month prevalence of major depressive disorder is approximately 6 % (Malhi and Mann, 2018). And depression is a risk factor for suicidal ideation and death (Ribeiro et al., 2018). The proportion of major depressive disorder recovered decreased significantly with the course of the disease, and the likelihood of relapse was high, with an increased risk in each episode (Verduijn et al., 2017). A recent systematic review in the Lancet reported that the COVID-19 epidemic increased by about 53 million depression patients in 2020, increasing by about 27.6 %. The prevalence of anxiety disorders increased by about 76 million (2021).

The clinical symptoms of depression range from mild to severe. Mild depression in the early stage is characterized by significant and persistent low mood and pessimism, while depression without active treatment could lead to stubborn insomnia, headache, memory loss, nausea, palpitations, chest tightness, sweating, and other physical symptoms (Park and Zarate, 2019). Therefore, identifying specific interventions that improve depressive status is critical for public health policy. A lifestyle factor-focused approach represents a cost-effective and practical strategy, and there is now compelling evidence that a range of lifestyle factors are involved in the pathogenesis of depression. Many of these factors can be modified, but they are rarely considered in contemporary depression treatment, where pharmacological and psychological interventions remain first-line treatments (Sarris et al., 2014).

Nutrition is a modifiable lifestyle factor. Current evidence suggests that adherence to healthy eating patterns, intake of specific nutrients, or consumption of specific foods can help prevent and treat depression and anxiety (Kris-Etherton et al., 2021). For example, a meta-analysis of 48 studies involving 2788 subjects showed that higher flavonoid intake might improve symptoms of depression (Ali et al., 2021). Since nutritional psychiatry's emergence, it has identified many mechanisms involved in psychiatric disorders, including inflammation, epigenetics, mitochondrial dysfunction, gut microbiota, and oxidative stress (Marx et al., 2021). Studies have shown that the “oxidative-antioxidant” function of the body in patients with depression is dysfunctional, mainly manifested in the increased concentration of oxygen free radicals and the abnormal activity of some antioxidant enzymes. Suppose copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GPX), and catalase (CAT) cannot effectively eliminate the oxygen free radicals produced by cell metabolism. In that case, the concentration of oxygen free radicals will increase, leading to abnormal structure and function of neurons, which might be one of the pathogenesis of depression. Studies have also shown that oxidative stress products are important parameters for measuring and predicting depressive status and determining the effectiveness of administered antidepressants (Vaváková et al., 2015).

Results from a series of observational and interventional studies in human have shown that multiple antioxidant supplements significantly affect depressive status (Das et al., 2021; Milajerdi et al., 2019). However, current randomized controlled trials (RCTs) are small sample studies focused on one or two specific antioxidants with inconsistent findings. The purpose of this study was to, first, analyze the effects of different types of antioxidant supplements on depression and anxiety, and second, to explore the direction of effects of this category of supplements on depression and anxiety by including as many antioxidant supplements as possible, and to quantify this effect. We also performed detailed subgroup analyses according to study country and type of depression and anxiety status assessment scales to minimize heterogeneity.

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