Alterations of serum macro-minerals and trace elements are associated with major depressive disorder: a case-control study

Major depressive disorder (MDD) is accompanied by low self-esteem and loss of interest or pleasure in day to day activities that adversely affect a person’s professional and personal life [1]. As major depression gives the enormous burden on an individual’s life, extensive efforts have been made to explore the biological mechanisms of it [2]. Major depression has been considered as a multifactorial disorder with genetic, neurological, and environmental factors contributing to overall risk. However, the mechanisms of these risk factors are still unknown [3]. Macro-minerals (MM) and trace elements (TE) play a versatile role in the biological system ranging from regulating metabolic reactions to acting as antioxidants [4, 5]. Several studies have suggested that alterations of these elements in serum levels are linked with the etiology and pathophysiology of many mental disorders [4, 6‐9], including major depression [10].

Calcium (Ca) is essential for activation of different enzymes and plays a vital role in neuromuscular excitability. Low Ca level in the blood serum causes fragility of hair and nails and can also lead to mood disorders and depression [11]. Thus the deficiency of this mineral in the human body is linked with several chronic diseases [12]. Magnesium (Mg) acts as a coenzyme for many enzymatic systems. Mg is considered as an important factor in the treatment of depression due to its regulatory effects on N-methyl-D-aspartate (NMDA) channels [11]. Chronic stress, alcohol abuse, a diet rich in carbohydrates and fats cause Mg deficiency in the human and prolonged deficiency of this mineral develops depression [13].

Copper (Cu) accumulates in the liver, muscles, skeletal system, and brain of the human. Our kidneys, liver, and coronary arteries can be damaged by the high concentration of Cu in blood serum. Although, many disorders occur in the circulatory system, nervous system, and digestive system due to the deficiency of Cu [14]. In the human body, iron (Fe) transports oxygen through hemoglobin [15]. Fe deficiency is manifested mainly in weakness due to the limiting of aerobic changes in muscles. Moreover, some authors associate a decrease in body temperature, low appetite, and restless leg syndrome with Fe deficiency [16, 17]. Manganese (Mn) is a crucial trace element for human health [18]. In the central nervous system (CNS), Mn is presents in several proteins and key enzymes which are associated with some neurodegenerative disorders [19‐21]. Selenium (Se) is an essential nutrient required for the functioning of antioxidant defenses in the brain and nervous system [22]. Zinc (Zn) is considered as an important element in the human body and sufficient amount of Zn is required for nucleic acid and protein metabolism, cellular growth, division and functions [23]. Zn is an important modulator of the functioning of the central nervous system [24].

Moreover, major depression can be influenced by some specific metalloenzymatic reactions in the brain. Trace metals regulate a range of cellular metabolic reactions and some of them are responsible for the etiology of several neurological disorders [25]. Superoxide dismutase (SOD) is a metalloenzyme that contains metal ions in its structure [26]. In human, three types of SOD are present. SOD₁ is cytoplasmic, SOD₂ is mitochondrial and SOD₃ is extracellular. SOD₁ is a dimer while SOD₂ and SOD₃ are tetramers. SOD₁ and SOD₃ contain Cu and Zn, while SOD₂ contain Mn at their reactive center [27]. CuZnSOD involved in defense against reactive oxygen species (ROS). MnSOD is an antioxidant enzyme that provides protection against free radicals [28].

Based on the above observations, the present study was undertaken to explore the associations of serum MM and TE levels with the risk of major depression on Bangladeshi population.

To the best of our knowledge, this is the first ever study on Bangladeshi patients to find out the association of serum MM and TE levels with MDD. The required amounts of MM and TE are essential for maintaining proper healthy life. The present study explored the associations of MM and TE with the risk of major depression, demonstrating that alterations of serum MM and TE levels are associated with the increased risk of MDD. This generally happens when usual neurological physiology is troubled [31].

Several studies have shown that lower levels of serum Ca and Mg can cause various symptoms e.g. depression, anxiety, behavior, and personality changes [32]. One study showed that the significant deficiency of Ca was found in depression [33]. Other studies reported that serum concentrations of Mg were found substantially reduced in depressed patients [34, 35]. Another study revealed that Mg rich diet reduces the depressive symptoms [36]. The severity of depression is significantly influenced by the serum levels of Mg which confirms the involvement of Mg in the pathogenesis of depression [37]. In our current study, we found significantly lower levels of serum Ca and Mg in MDD patients compared to control subjects (p < 0.05). Thus this downregulation of serum MM levels may be involved in the pathogenesis of MDD.

The average concentration of serum Cu was found higher in depressed patients by 21% than healthy controls [38]. In our study, we also found the higher concentration of Cu in MDD patients compared with the control subjects (p < 0.05). Fe plays a major role in the development of the central nervous system (CNS). Moreover, it plays a crucial role in the development of depression as fatigue is caused by Fe deficiency. The current study found that the serum levels of Fe were reduced significantly in MDD patients which are supported by previous study results [39]. Low levels of Mn cause depression by increasing auto-immune reactions and macrocytosis [40]. In our present study, we found the significantly lower concentration of Mn in MDD patients compared with the control subjects (p < 0.05). Another valuable element is Se and any deficiency of this element causes the glutathione peroxidase dysfunction which is an enzyme that protects oxidative damage [41]. Also, Se modulates the status of many neurotransmitters [42]. Lower Se concentration is a risk factor for depression via antioxidant pathways [43]. According to our study, Se concentrations were significantly lower in MDD patients compared with the controls (p < 0.05). This evidence suggests that Se deficiency contributes to the pathogenesis of MDD as it prevents oxidative damage. Zn deficiency in humans is relatively rare but it occurs during the emotional stress and some disease conditions e.g. giardiasis, diarrhea, acute pancreatitis, and chronic renal failure. Several studies have suggested that prolonged Zn deficiency causes neuropsychiatric disorders such as depression and lack of concentration [43‐45]. These observations are consistent with our present study result where a significantly decreased level of serum Zn was found in MDD patients (p < 0.05).

Nearly 7.6% patients suffering from psychiatric disorder have nutritional problems [46]. Serum concentrations of MM and TE are known to be influenced by dietary factors. The effects of diet on serum level of MM such as Ca and Mg are sparse [47]. Serum levels of Fe and Zn are especially affected by diet [48]. Serum level of Se could be affected by the low Se containing foodstuffs [49]. Deficiencies of Cu and Mn in the serum level are unusual due to a wide variety of dietary sources [50]. Pharmacotherapy is also a considerable factor that influences the serum levels of MM and TE in MDD patients. Serum Cu level is influenced by acute antidepressant therapy such as escitalopram and reboxetine reduced and imipramine increased serum Cu level [51]. Decreased serum Zn concentration can be normalized after successful antidepressant therapy e.g. citalopram increases serum Zn level [52].

At the end of our discussion, we can give some outline about lifestyle and diet as interventional events for MDD. According to our study findings, we can propose diet, current pharmacotherapy, and lifestyle as considerable factors for the proper treatment of MDD. We did not investigate the impact of dietary supplementation, current pharmacotherapy, and lifestyle on our study parameters that were the main drawback of our study. Therefore, this is a preliminary study and further investigation with more homogenous samples is required to support our findings. In spite of these limitations, the present study has some significant advantages. The first strength is the large study population match on age, sex and residential areas of patients and healthy controls. Another one is the simultaneous determination of all macro and micro elements under the same experimental conditions.

The present study illustrates that MDD patients have reduced serum concentrations of MM and TE except for Cu compared with healthy volunteers. So these findings suggest the possible involvement of depleted serum MM and TE in the pathogenesis of depression. It was found that there was no significant correlation of serum MM and TE with age and BMI of the patient group. The reduced serum MM and TE may have an influence on the development of MDD. We thus recommend the altered serum levels of MM and TE are associated with the risk of MDD which may require further study.