2.1. Dietary Sugars
Glucose is the primary source of energy for the human brain. ATP produced by glucose metabolism is the basis for maintaining neuronal and non-neuronal cell functions in the brain, such as producing neurotransmitters and nerve impulses [9]. Most sugars are metabolized in the body to produce glucose. There are many sugars in sweets, beverages, and candies. Many studies have shown that the excessive intake of sweets, sugar-sweetened beverages, and candy increases the risk of depression. Guo et al. have shown that regular consumption of sugar-sweetened beverages might increase the risk of depression in older Americans [10]. A study by Vermeulen et al. in a Dutch population also showed that a dietary pattern high in sugar (HS) increases the risk of depression [11]. The result of a 3-year follow-up survey by Shimmura et al. showed that high candy consumption significantly increases the risk of depression among Japanese workers, with 16.8% of high candy eaters experiencing depressive symptoms [12]. A study by Kashino et al. also showed that Japanese people who drink ≥4 cups of sugar-sweetened beverages per week have a 91% higher risk of depression than those who drink <1 cup/week [13]. A meta-analysis study indicated that people who consume 2 cups of cola per day have a 5% increased risk of depression, while those who consume the equivalent of 3 cans of cola per day have an approximately 25% increased risk of depression [14]. The research among Chinese people has also demonstrated that a high-sugar diet increases the odds of depression [15,16]. A study in the Spanish population found that consumption of added sugars was associated with a significantly increased risk of depression but no significant association between the consumption of sugar-sweetened beverages and the risk of depression [17]. A study on the Korean population suggested that beverage intake increases the risk of depression in women but decreases the risk in men. The differences may be due to different statistical methods for sugar intake and evaluation criteria for depression [18]. Moreover, a high-sugar diet is prone to diabetes and obesity, which are also risk factors for depression [19,20]. In addition to sugar, sugary drinks and desserts may add sweeteners and other ingredients, the excessive intake of which may also be associated with the occurrence of depression, but there is currently a lack of relevant research with follow-up studies. A study has shown that fasting blood glucose concentrations (FBG) were significantly elevated in major depressed patients compared to healthy subjects (4.73 ± 0.45 vs. 4.52 ± 0.43 mmol/L, p < 0.01) [21].
The possible physiological processes and physiological components of a high-sugar diet affecting depression might be considered in the following pathways: 1. Neural signals: it affects the content of 5-Hydroxytryptamine (5-HT) in the brain. Animal experiments showed that a high-sugar diet reduces the activity of dendritic 5-HT-1A receptors, which may impede the feedback control of serotonin synthesis and release in the hypothalamus leading to a decrease in 5-HT [22]. 5-HT is a crucial monoamine neurotransmitter, and its decreased content in the brain is one of the critical factors leading to depression [23]. 2. Inflammation and pro-inflammatory factors. A meta-analysis study by Köhler et al. indicated that pro-inflammatory factors such as interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), interleukin-13(IL-13), interleukin-12(IL-12), etc., are significantly elevated in major depressive disorder (MDD) patients, which associates inflammation with depression [24]. Lipopolysaccharide (LPS) is a commonly used inflammatory inducer. Experimental studies have shown that LPS induces inflammation in rodents at the same time as depression-like symptoms [25,26], indicating there might be a correlation between inflammation and depression. Do et al. showed that a high-sugar diet could induce inflammation and depression-like behavior in mice. Moreover, they found that a high-sugar diet may induce inflammation by altering the gut microbiota and intestinal permeability [27]. 3. Synaptic plasticity and the expression of brain-derived neurotrophic factor (BDNF). The level of BDNF in the serum of patients with MDD is significantly lower than that of healthy patients, and after receiving antidepressant treatment, the level of BDNF in the patient’s body is significantly increased. BDNF can be used as a biomarker of depression or as a measure of antidepressant efficacy predictors [28]. Another study showed that low plasma BDNF is associated with suicidal behavior in major depression [29]. BDNF is widely expressed in the developing and adult mammalian brain and has been implicated in development, neural regeneration, synaptic transmission, synaptic plasticity, and neurogenesis [30]. A deficiency of BDNF or Trk receptors does not induce depression, but antidepressants are required to increase BDNF activity and restore neuronal networks [31]. In rodent models, a high-glucose diet can reduce the expression of BDNF, synapsin I, cyclic AMP-responsive element-binding protein (CREB), and growth-associated protein 43, which affect synaptic plasticity [32]. Another study showed that after one week of feeding rats with high sugar and fat, dendritic spines and dendritic branches in the CA1 region of the rat brain were significantly reduced [33].