Introduction
Children’s malignancies account for about 2% of all malignancies each year, and 15.3 people per 100000 people under the age of 20 get cancer every year [1]. During the last 50 years, the 5-year survival rate in children with cancer has increased from 10%-20% to 80%-85% [2]. With the increase in life expectancy in patients with cancer, the treatment approach includes other aspects of children’s lives in addition to treating the disease and maintaining survival [3]. The rate of adjustment disorders, depression, and anxiety in patients with cancer has been estimated between 16% and 42% in different studies [4]. Meanwhile, depression is considered a crucial complication in disrupting the quality of life of children with cancer.
If childhood depression is not properly diagnosed and treated, it increases the possibility of drug abuse, suicidal behavior, and psychological, social, and academic dysfunction of the child [5, 6]. Researchers have shown that the symptoms of depression at the age of 10-11 years using children’s depression inventory (CDI) predict the complications of mental problems (especially aggression), poor adaptive performance, and low self-confidence in youth [7]. The lower the age of onset of depression, the poorer the prognosis [8]. At any time, 10%-15% of children in the general population report moderate to severe depressive symptoms [9].
As a micronutrient, zinc plays a vital role in various body activities. Disturbance in the regulation of zinc metabolism is associated with immune disorder, growth disorder, and gastrointestinal complications [10, 11, 12, 13, 14, 15]. The human body contains 2 to 3 mg of zinc, most concentrated in the hippocampus, amygdala, and frontal cortex, which deals with emotions [10]. In addition, studies have shown that taking zinc supplements improves mood in people under antidepressant treatment and normal people [13].
In this study, while evaluating the level of depression in children with cancer, the effect of zinc supplementation on the depression of these patients was evaluated by prescribing zinc supplements to patients with zinc deficiency.
Materials and Method
This study was a clinical trial (before and after) that was conducted in the Children’s Blood and Cancer Department of Bo Ali Sina Hospital in Sari City, Iran. The studied patients included 5 to 18 years old children with malignancy referred to this hospital for treatment. This study has been registered with the ethical code ID IR.MAZUMS.REC.1398.1182 by the Ethics Committee of Mazandaran University of Medical Sciences and with the code IRCT20190202042583N1 in the Iranian registry of clinical trials. 
The inclusion criteria included those between 5 and 18 years suffering from malignancy under chemotherapy treatment, consent to participate in the study, and to test the serum level by taking two blood samples. The exclusion criteria included passing more than one month since the last round of chemotherapy, taking antidepressants of any category during the past month, taking zinc supplements or other supplements containing zinc compounds during the last month, congenital diseases of zinc metabolism disorder, such as acrodermatitis enteropathica, chronic inflammatory bowel disease, suffering from malabsorption syndromes, incomplete completion of the questionnaire form, irregular use of antidepressants, or zinc supplement.
The sample size included 76 people based on the previous studies, α=0.05, and β=0.2 [16]. The work steps were planned in a way that was coordinated with the children’s chemotherapy sessions. In the first session, all aspects of the study and the voluntary nature were explained. After obtaining written and verbal consent from the patients and the parents, the patient was asked to complete the Maria Kovacs CDI [14] alone or with the help of the parents. This questionnaire, validated in Persian for children in Iran, includes 27 questions about different feelings and thoughts. The answer to each of the 27 questions is scored based on the absence of a symptom (score 0) to the presence of a specific symptom (score 2). According to the number of questions and the scoring of each question for this questionnaire, the range of score has been considered 0 to 54, and a higher score indicates greater severity of depression in patients, and based on this questionnaire, a score of 0 to 8 was considered healthy, and a score of 9 to 19 on the threshold of depression and a score of 20 and above was considered depressed.
After obtaining consent and completing the questionnaire, the level of the patient’s serum was measured on the same blood sample taken for routine tests before chemotherapy so that it is not required for separate blood sampling for the study. Each patient’s questionnaire was examined separately during the study, and the patients were grouped according to the questionnaire into three groups: healthy, on the threshold of depression, and depressed. The serum level of each patient was measured separately during the study, and then the serum level of all three groups was compared. The normal serum zinc level was considered 84 to 160 μg/dL, and those below 83 μg/dL were treated with zinc supplementation [14]. The zinc measurement test was performed on the serum sample using the “Biorexfars” kit and the automatic atomic absorption spectrophotometry method.
Patients on the threshold of depression and depressed patients were referred to a psychiatrist based on a questionnaire to decide on the treatment of depression (according to the child psychiatrist in this study, no child was a candidate for antidepressant medication).
Patients with zinc deficiency (100% of the children participating in this study had zinc deficiency) were treated orally with 10 mg of zinc gluconate (NeoZink syrup) daily (recommended dietary allowance [RDA] value between the ages of 5 and 18 years) for one month [14]. At this stage, the exact date of starting the medication was recorded for each child separately, and how to take the medication was explained to the family. One month after starting the medication, a standard CDI test was performed on all patients, and the serum level was measured again.
The data were analyzed using SPSS v. 20 software, and the normality of serum zinc level (quantitative continuous variable) was checked using the Kolmogorov-Smirnov test, indicating the normal distribution of serum zinc level. Quantitative data were reported as Mean±SD. To compare the quantitative data with a normal distribution, we used the paired t test, and to compare the qualitative data, we used the Chi-square test. Also, to check the variables with a non-normal distribution, the Mann-Whitney test was used. A significance level of P<0.05 was considered for all tests. The criterion for diagnosing zinc deficiency in the fasting state was 84 μg/dL.
Results
Out of 76 children in the study, 69 children with cancer referred to the Oncology Department of Bo Ali Sina Hospital in Sari City were examined. Two patients were excluded from the study due to reluctance, and three patients due to partial completion of the questionnaire (Figure 1). The average age of the children was 8.40±5.10 years. A total of 40 children (58%) were boys, and 29 (42%) were girls.
One hundred percent of children with cancer suffer from zinc deficiency. The mean zinc serum level before the intervention in children with cancer was 77.26±25.60 µg/dL, and the mean zinc serum level after the intervention was 81.25±26.35 µg/dL. No statistically significant difference was observed between the mean serum zinc level before and after the intervention (P=0.192).
The serum level of zinc before and after the intervention in the patients of the depression threshold group had a statistically significant difference (P=0.042). However, no statistically significant difference was observed in serum zinc levels before and after the intervention between normal and depressed patients (P=0.885) (P=0.661) (Table 1).


The results obtained from the study showed that all 6 depressed children had acute lymphoblastic leukemia (ALL) and 79.5% of children with borderline depression had ALL, and 52.6% of normal children had ALL. Among the children at the threshold of depression, 2 children (4.5%) were diagnosed with neuroblastoma and 4 (9.1%) with lymphoma. Based on the Fisher test, the frequency of depression was not significantly related to the type of cancer (P=0.301).
No statistically significant difference was observed between the two genders in the average serum zinc level before the intervention (P=0.654). The average zinc serum level between the two genders after the intervention is not statistically significant (P=0.88) (Table 2).


The average zinc serum level before the intervention in children with ALL was 27.35±76.16 µg/dL; the average zinc serum level before the intervention in children with neuroblastoma was 79.67±20.20 µg/dL; the average level of serum zinc before the intervention in children with lymphoma was 78.09±14.48 μg/dL, and the average zinc serum level before intervention in children with hepatoblastoma was 97 μg/dL. Also, the average zinc serum level before the intervention in children with osteosarcoma was 130 μg/dL, and the average zinc serum level before intervention in children with germ cells was 76 μg/dL. The average zinc serum level before the intervention in children with rhabdomyosarcoma was 46 μg/dL. No statistically significant difference was observed between different cancers before the intervention in the average zinc serum level (P=0.750). No statistically significant difference was observed between different cancers after the intervention in the average zinc serum level (P=0.07) (Figure 2). No statistically significant difference was observed in the average serum zinc level before and after the intervention in the normal group in terms of depression. Also, no statistically significant difference was observed in the average serum zinc level before and after the intervention in the threshold of depression group. Also, no statistically significant difference was observed in the average serum zinc level before and after the intervention in the depressed group (P=0.153).
The results obtained from the study showed that out of 6 depressed children, 4 children (66.7%) were boys, and 2 children (33.3%) were girls. Girls with cancer had depression more than boys with cancer. A statistically significant relationship was observed between the depression and male gender (P=0.015)
The results obtained from the study showed that out of 6 depressed children, 4 (66.7%) were in preschool, and 1 (16.3%) was in middle school. No statistically significant relationship was observed between depression and level of education (P=0.068).
In addition, the results obtained from the study showed that out of 6 depressed children, 4 (66.7%) lived in the village, and 2 (33.3%) lived in the city. No statistically significant relationship was observed between depression and place of residence (P=0.121).
The results obtained from the study showed that the average weight of depressed children was 35.33±28.85 kg, and the average weight of normal children was 21.311±63.41 kg. Also, the results showed that the average age of depressed children was 8.16±5.8 years and the average age of normal children was 10.52±4.4 years. Depression had no statistically significant relationship with weight and age (P=0.099, P=0.069, respectively).
Discussion 
This study is a clinical trial study that was conducted on 69 children with cancer to evaluate the effect of zinc supplementation on reducing depression in these patients.
Zinc is one of the most abundant essential rare elements in the human body, found in all tissues. Zinc deficiency causes sensory disturbances and inefficiency of the immune system, atherosclerosis, increased oxidative stress, delayed physical and mental development in infants, and causes a decrease in reproductive performance and productivity in adults [17]. Zinc is one of the rare, vital elements in the body, a crucial structural component of more than 200 metalloenzymes involved in cell proliferation pathways, DNA repair, antioxidants against free radicals (factors involved in causing cancer), such as zinc/copper superoxide dismutase enzyme, etc., as well as APA1 protein carries zinc cofactor by binding to telomerase enzyme gene promoter (responsible for the unlimited proliferation of cancer cells) reduces its expression [18]. Long-term zinc deficiency leads to neurobiological changes, such as emotional disorders and irritability, and depression. Factors such as consumption of grains with high fiber and phytate, such as bread and rice, iron supplements, gastrointestinal diseases, smoking, and stress change plasma zinc concentration [19].
The normal serum zinc level is around 84 to 120 μg/dL [15]. The results obtained in this study showed that 6 children (8.7%) with cancer suffered from depression. Also, the prevalence of zinc deficiency in children with cancer was 100%. In fact, the frequency of zinc deficiency was much higher than in other studies. The biological role of rare essential elements, especially the changes in the levels of the body in various cancers, has been considered by various research teams in recent years [20, 21]. In the study by Sagabera et al. in Brazil, a developing country like Iran, the serum level of zinc in children with leukemia was reported to be 73.3 compared to 93.6 in healthy people [22]. In this study, 100% of children with cancer had zinc deficiency, and the serum zinc level in children with cancer was 77.28, similar to Sagabera’s study.
The studies conducted by Zuo et al., similar to the present study, indicate that in people with ALL, the concentration of zinc in the serum is lower than that in normal children [23]. In this study, as in the study by Zuo the serum level of zinc in children with cancer was lower than in the normal population, and the results of this study are similar to the results of Zuo’s study.
In this research, 3 main reasons can be mentioned to justify zinc deficiency in cancer patients. First, blood cancer or applied methods to treat it may lead to anorexia, poisoning, nausea, malnutrition, or malabsorption syndrome, each of which can be considered a reason for zinc deficiency. The harmful effects of chemotherapy are also the cause of zinc deficiency in these patients [24].
A third reason to consider is the possibility that a person has had a zinc deficiency before the onset of leukemia. Maret et al. state that one-third of the world’s population is at risk of zinc deficiency [25]. The lack of zinc in normal people can be justified due to the lack of zinc in the soil and plant products, especially in third-world countries [26]. Also, the diet of Iranian people contains large amounts of phytate and a small amount of zinc [27].
In our study, no statistically significant difference was observed between the serum level of zinc before the intervention compared to patients in the healthy group and those on the threshold of depression and depressed. No statistically significant difference was observed in the serum level of zinc after the intervention in the patients of the healthy group and those on the threshold of depression and depressed. The result of the research of Zuo and his colleagues indicates that in patients with leukemia and undergoing chemotherapy who also received zinc supplements, after the completion of the treatment period, the serum level of zinc is similar to normal people [23]. After receiving a zinc supplement for 1 month in the form of 10 mg of zinc gluconate (neozinc syrup), the results of this study showed that children with cancer, did not differ in the level of zinc before and after the intervention. This result was consistent with the study conducted by Xuan Zou et al. [23].
Anbari-Nogyni et al. [28] conducted a study on 297 elderly people. In this study, the serum level of zinc and the amount of zinc in the diet were measured over three days, and depression were assessed with the geriatric depression questionnaire. The results showed a significant statistical relationship between the incidence of depression and zinc serum concentration, and the incidence of depression and zinc serum deficiency in the elderly was reported to be high. In this study, the level of zinc intake through the 3-day diet was not related to the degree of depression. In another study conducted on 100 elderly people, similar results were obtained from the study of Anbari-Nogyni et al. The study showed that people living in nursing homes are at risk of zinc deficiency, and this serum index is related to mental health status [28, 29].
In the study conducted by Ghayour-Mobarhan  et al. on 3768 men, it was shown that the average serum level of zinc was not related to depression in men. The results of Darroudi’s study are consistent with the present study [30].
Two studies investigated the effectiveness of zinc supplementation as an antidepressant medication supplement (imipramine) in treating depressive symptoms. The criteria measured by Nowak et al. [31] study were the Beck Depression Inventory and the Hamilton Depression Rating Scale. The measurement tools in Siwek et al. [32] study were also the Beck depression inventory and the Hamilton depression rating scale, the clinical global impression score questionnaires, and the Montgomery–Åsberg depression rating scale. After 12 weeks of follow-up, a significant difference was seen in all measurable prognoses of depressive symptoms between placebo and zinc supplementation in both studies. Subgroup analysis in the study by Siwek et al. [33] regarding the effect of zinc supplementation in patients resistant to antidepressant treatment showed that patients who recently showed resistance to antidepressant treatment had a lower depression score after using zinc supplementation compared to the placebo group [31, 32, 33]. Also, one studies have investigated the effectiveness of zinc supplementation in the prognosis of depressive symptoms in non-depressed women. In addition to depression symptoms, the effect of zinc supplementation on other psychiatric disorders, such as anxiety, aggression, and tension, was also investigated. These studies showed that zinc supplementation improved all mood disorders (major depressive and anxiety disorders) [34].
In the study by Nguyen et al. [35], which investigated the effectiveness of microbrain supplements in preventing depressive symptoms, no statistical relationship was reported between the use of microbrain supplements and depressive symptoms. In this study, zinc supplementation was used to treat depression in children with cancer. The results showed that after the treatment period, the use of the supplement did not differ in the depression score before and after the intervention, and it was consistent with Nguyen’s study. 
Nowak et al. [31] examined the effect of zinc supplementation as adjunctive antidepressant treatment in depressed patients over 12 weeks. The level of depression in patients receiving zinc supplements from the second to the twelfth week was significantly reduced compared to the control group. Nowak et al. suggested zinc supplementation as an adjunctive treatment for depression. To examine the relationship between zinc serum levels and depression in adult depressed patients, a study was conducted. In several animal studies, it was shown that the administration of zinc compounds has antidepressant effects in the forced swimming test. It was reported in this study that the concentration of zinc in the serum of depressed patients is lower than in healthy individuals, and a significant relationship was observed between the concentration of zinc in the serum and the severity of depressive symptoms.
On the other hand, zinc supplements can strengthen the effect of antidepressants. Zinc is an important modifier of receptors and channels in the nervous system. For example, zinc inhibits N-methyl D-aspartate, gamma-aminobutyric acid, and nitric oxide synthase receptors, which are the targets of antidepressants, while increasing the activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid channels [35, 36, 37, 38, 39].
Conclusion
Considering the very high frequency of zinc deficiency in children with cancer and the role of its antioxidants in malignancy, according to studies, necessary measures should be taken in this regard. Given that zinc deficiency in children with cancer is considered a serious problem, more extensive studies in this field are recommended to investigate the exact amount of zinc deficiency in these patients, considering factors such as the type of disease, gender, and age. Also, in this study, zinc consumption did not affect the treatment of depression, which requires further study to investigate the treatment period or increase the dosage of zinc to investigate the effect.

Ethical Considerations
Compliance with ethical guidelines
This study has been registered with the ethical code ID IR.MAZUMS.REC.1398.1182 by the Ethics Committee of Mazandaran University of Medical Sciences and with the code IRCT20190202042583N1 in the Iranian registry of clinical trials

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions
Nceptualization and Supervision: Hossein Karami ,Maryam Rezapour and Mohammad Naderisorki; Methodology: Mohammad Naderisorki; Data collection: Shadi Etehadie; Data analysis: Mohammad Naderisorki; Investigation, Writing–original draft, and Writing–review & editing: All authors.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
We sincerely thank and appreciate all the children with cancer and their families who participated in this study.


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