The inverse correlation between serum zinc levels and depression severity in Egyptian adolescent students: a case–control study

Depression is a psychiatric disorder with high morbidity and mortality. It contributes to 50–70% of suicides causes [1].

According to research, adolescent depression is an early-onset subtype of the corresponding adult condition and has a substantial correlation with recurrence later in life. Similar clinical characteristics and patterns of brain activity characterize the condition in adolescents and adults. Adolescent depression frequently goes undiagnosed and untreated, despite its significant repercussions [2, 3].

The increasing number of studies indicate a strong association between unhealthy eating habits and poor mental health outcomes in children and teenagers. Inferences about a causal relationship between food and depression in this group, however, should be made with attention due to a paucity of prospective evidence. For individuals prone to depression, changes in biochemical and regulatory systems, such as oxidative stress and immune-inflammatory pathways, can contribute to the condition. Additionally, an unhealthy diet may also trigger depression [4].

Generally, a high-quality diet is associated with improved mental health overall, reduced incidence and severity of depression, and lower food intake, according to a recent systematic study. Researchers have also discovered a link between children's depressive symptoms and poor nutrition quality [4].

Specifically, zinc is one of the trace elements that is necessary for all living things. It has a significant function in depression treatment and psychopathology. Zinc is essential for protein synthesis, transcription, and DNA replication, all of which affect cell division and differentiation. Zinc deficiency in the diet slows down the growth of both humans and animals [5].

Besides, Zinc deficiency affects the homeostasis of zinc in the brain, which changes behavior, learning, mental function, and increases the risk of epileptic convulsions. Insufficient dietary intake or low zinc levels in the blood have been shown to contribute to depression among female students, zinc is a necessary cofactor for maintaining the regular operations of numerous enzymes with critical functions in the brain and is involved in several numbers of protein structural elements [6].

Therefore, this study aimed to evaluate the possible association between serum zinc and depression in adolescent students. The research question was “Is there difference between zinc serum level between depressed and normal adolescents? “It is postulated that serum zinc level negatively correlates with depression score. Our hypothesis that there is an inverse correlation between zinc levels and depression severity is based on the clinical evidence in the meta-analysis of 17 clinical studies showing that blood zinc concentration in depressed individuals is significantly lower than in non-depressed controls [7].

Adolescent mental health disorders were associated with increased comorbidity, a decline in life quality, and a greater burden on the person, family, and community. Therefore, looking into the role nutrition plays in teenage psychopathology may assist in lessening the severity of the condition and speeding up recovery.

The sample size was calculated using G power version 3.1.9.7 software (SPECS, 2020) power 95%. The calculated sample was 86 students (43 cases and 43 controls). The sample was multiplied × 2 design effect due to design dropout and analysis of multivariable to become 172 students (86 cases and 86 control).

Inclusion criteria were Students in the preparatory and secondary schools aged between 12 to 18 years old. Exclusion criteria were students with a history of psychological problems rather than depression or those known to have chronic diseases by asking the caregiver during the interview, students taking medications for depression, or any long-term medications, and those taking vitamin/mineral supplements.

After explaining the aim of the study and the way of filling the Arabic version of a 21-question Beck's questionnaire to participants by the researcher and 2 assistants, the student filled out the questionnaire.

This self-report questionnaire is used to evaluate the intensity and breadth of depression symptoms in The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. The interpretation of the questionnaire is (0–9: no depression, 10–15: mild depression, 16–23: moderate depression, 24–36: severe depression, and more than 37 very severe depression).

All the students who had positive scores (mild to severe depression) were considered as cases (86 from 109 as 23 cases refused to do the serum zinc level) and a matched number of students (86) with a normal or negative score on the Beck questionnaire were considered as controls. The research team also called the caregiver to confirm the time of arrival to collect venous blood samples from the students under study at a particular district laboratory.

Written consent from the students’ caregivers who agreed to participate in the research was obtained to draw 5 ml of venous blood using a plastic syringe and a stainless-steel needle. The blood was drawn into a metal-free plastic tube, allowed to clot at room temperature for 30 min, and then centrifuged for 15 min at 3,000 rpm in a room with no dust. Prior to analysis, serum samples were shielded from light and kept at 80 °C. Normal serum zinc level was 60–130 µg/dl in adolescents [8]. The analysis was done by Robonik Readwell Microplate Elisa Reader, which was made in China in 2016.

After filing the written consent from the caregivers of the students, the parents completed the Gilany Socioeconomic Questionnaire (SES) [9].

Statistical analysis: Data entry was completed using the Excel program and the SPSS 26.0 for Windows (SPSS Inc., Chicago, IL, USA). The mean and standard deviation were used to convey quantitative data. Independent samples Student's t-test, one way ANOVA test, and Chi square test were employed. Person rank correlation coefficient was calculated, whereby the validity of the tested variables was assessed by roc curve (P-value < 0.05 was considered statistically significant (S), while p-value ≥ 0.05 was considered statistically insignificant).

Of the 358 students, 109 students (30.4%) had depression according to the used questionnaire (23 of them were excluded as they refused to do any investigations) and 249 of them (69.6%) had no depression (normal). 86 cases and matched 86 from the normal students were selected as controls.

The analysis showed a statistically significant difference between the depression classifications regarding mean SES total score and sex where cases with moderate depression were either from low social class or middle social class, and the majority of cases with moderate depression were females (Table 1).

The majority of the studied group were within normal serum zinc levels. As shown in Table 2, there was a statistically significant difference between the studied groups when comparing depression grade and serum zinc. Depressed group cases had lower mean values of serum zinc.

Thirdly, Table 3 demonstrates a statistically significant difference between the depression classifications and zinc as cases with moderate depression had lower mean values of zinc. On the other hand, there was no significant difference between cases with mild and moderate depression.

Table 4 presents the predictive values of zinc level in depression prediction. The Area Under the Curve (AUC) is 0.673, indicating a moderate level of accuracy in distinguishing between depressed and non-depressed individuals. The 95% Confidence Interval (CI) ranges from 0.593 to 0.753, suggesting variability in the predictive power. The cutoff value for zinc level is 104.5, with a sensitivity of 64% and specificity of 60.5%. This means that the test correctly identifies 64% of true positives (individuals with depression) and 60.5% of true negatives (individuals without depression). The Predictive Value for Positive (PVP) is 61.8%, and the Predictive Value for Negative (PVN) is 62.7%, indicating the likelihood that individuals identified as positive or negative by the test truly have or do not have depression, respectively. The overall accuracy of the test is 62.2%. These values suggest that while zinc level has some predictive value for depression, it is not highly accurate and should be used in conjunction with other diagnostic tools and clinical assessments.Table 5 shows the correlations highlight the relationships between socioeconomic status, zinc levels, and depression severity. The table highlights important relationships between socioeconomic status, zinc levels, age, and depression severity. Clinically, it suggests that improving SES and zinc levels could potentially help in reducing depression severity.

Females are more prone to depression, and yet higher levels of zinc are protective factors against depression (Table 6). The negative coefficient and odds ratio of less than 1 suggest that higher zinc levels are associated with a reduced likelihood of depression and indicate that sex and zinc levels are significant predictors of depression, while age is not. The findings suggest that being of a particular sex (female) significantly increases the risk of depression, and higher zinc levels are associated with a reduced risk of depression.

Serum zinc was still a predictor of depression after adjustment of age and sex as shown in Table 7.

This study aimed to assess the possible association between zinc deficiency and depression among adolescent students aged 12 to 18 years. In the current study, by using the Arabic version of the Beck questionnaire of depression, the prevalence of depression was 30.4% when compared to similar studies in a study conducted in South Sinai by Salah and colleagues [10]) which showed a high prevalence of depressive symptoms among public schools ‘adolescents (41.9%). A Malaysian study conducted by Wahab and colleagues [11] stated that the prevalence of depression was 39.7% and an Iranian study conducted by Daryanavard and colleagues [12] reported that the prevalence of depression was 31.30%.

On the other hand, some other studies reported a much lower prevalence. For example, a study conducted in secondary schools in Eastern Cairo by El-Missiry and colleagues [3], the prevalence was 21%. So, teenagers in impoverished countries have a greater chance of developing mental health problems. our results were compatible with those of El-Missiry and colleagues [3], who indicated that low socioeconomic status is a predictor of depressive symptoms. Their study demonstrated that depression rates are higher among individuals with low socioeconomic status, with a prevalence of significant depression symptoms found to be 21% among the adolescent girls studied. This finding is in line with that of Lemstra and colleagues [13] revealing that youth with low socio-economic status are approximately two and a half times more likely to suffer from depressed mood or anxiety than other youth from a higher socio-economic status.

The current study revealed that the mean Zn level was within the normal range in both cases and controls. However, it was 8 ug/dl lower in depressed students than in healthy students. There was a statistically significant difference between the studied groups when comparing depression grade and zinc as depressed group cases had lower mean values of Zn. The potential mechanisms underlying the association between low serum Zn and depression remain unclear, but Wang and colleagues [14] illustrated that it may involve the regulation of neurotransmitter, endocrine, and neurogenesis pathways. According to Takeda and colleagues [15], rats fed a diet low in zinc developed elevated blood cortisol concentrations. The development of depression has been linked to persistently elevated cortisol levels through the hyperactivity of the hypothalamic-pituitary–adrenal (HPA) axis. Therefore, elevated plasma cortisol levels may mediate the connection between depression and zinc insufficiency.

The results of a double-blind clinical experiment by Ranjbar and colleagues [16] to examine the effects of 25 mg zinc augmentation to selective serotonin reuptake inhibitors (SSRI) in the treatment of depression were in line with this conclusion,the results of this study showed that major depressive disorders were much improved when zinc therapy was taken in addition to SSRI antidepressants. They suggested that taking zinc therapy may lessen the levels of inflammatory cytokines and increase brain-derived neurotrophic factor (BDNF), which may lessen the severity of a major depression.

Furthermore, a meta-analysis of 17 observational studies by Swardfager and colleagues [7] revealed that the blood zinc concentrations of depressive individuals were roughly 0.12 µg/mL lower than those of control participants.

Maserejian and colleagues [17] demonstrated that a low dietary or supplemental zinc intake was reported to contribute to depressive symptoms in women, but not in men.

Some studies have similarly shown a negative association between dietary zinc intake and depression. Yary and Aazami [6] carried out a research project to look at the connection between zinc intake from food and depression. Even after controlling the factors such as age, sex, level of education, smoking, status, and level of physical activity, they discovered a negative correlation between dietary intake of zinc and depression. In two sizable prospective cohorts, Vashum and colleagues [18] investigated the impact of dietary zinc as a predictor of incident depression. The researchers found that a higher frequency of depression in both men and women is linked to a reduced dietary intake of zinc.

The study's limitations are that it was a case–control study, so more randomized controlled trials are needed. Only secondary school students were included, leaving out younger adolescents in preparatory schools. We suggest further research on other micronutrients and their link to depression, as this study only looked at zinc.”

Serum zinc levels were inversely correlated with depression in adolescent students. There was a statistically significant negative correlation between depression severity and each SES Level and zinc. Zinc was a predictor for depression with a cut-off level of 1.95 mg/dl. We suggest directions for future research, such as longitudinal studies to explore the causal relationship between zinc deficiency and depression.