Dietary Supplementations and Depression

Introduction

Depression is a mood disturbance condition that lasts for more than two weeks in a row. As per the United States Department of Health and Human Services, the prevalence of depression is 8.7% in individuals aged between 18 and 25 years.¹ Approximately, 264 million people worldwide suffer from this disorder.² It is characterized by sadness, feelings of worthlessness or guilt, appetite changes, sleep problems, fatigue, loss of interest, aimless physical activities or slowed movements, thinking challenges, and worst of all, suicidal thoughts.³ Depression can also lead to reduced activities levels, hampering the ability to work and study. Suicide is the worst impact of depression, causing the deaths of; >700,000 people every year. Suicide is the fourth leading cause of death among 15–29-year-olds.⁴

Depression has several types, including depressive disorder (clinical depression), bipolar disorder (manic depression), persistent depressive disorder (dysthymia), and seasonal affective disorder (SAD).⁵ A potential cause of major depressive disorder (MDD) is an inflammatory reaction in the hippocampus.⁶ MDD can also occur due to bad life experiences. Child abuse, neglect, and loss increase the risk of MDD in adulthood.⁷ The exact cause of bipolar disorder (manic depression) is unknown, but several factors may contribute such as biological differences and genetics. Biological differences include circadian dysregulation of mood disorders, Circadian Locomotor Output Cycles Kaput (CLOCK) protein and Brain and Muscle ARNT-like Protein 1 (BMAL1), and pharmacological triggers like tricyclic antidepressants (TCAs).⁸ The existence of complex interactions between neurotransmitters and receptors that affect the brain’s chemical moods play a role in persistent depressive disorder. Neurotransmitters that affect mood include dopamine, epinephrine, norepinephrine, GABA, and glutamate,⁹ which are the neurotransmitters in question. The exact cause of SAD is unclear, but it may be due to chemical changes in the brain attributable to inadequate sunlight and shorter days. Additionally, melatonin may also be associated with SAD.¹⁰

Depression can be treated with antidepressants that are categorized into five groups, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors, and non-TCA antidepressants.¹¹ These treatments are effective;^12,13 however, meta-analytical studies have found low remission rates,¹⁴ and antidepressants and placebo drugs only provide clinically significant differences in patients with upper-end severe depression. The reason for the skepticism with regard to the prescription of antidepressant drugs is their addictive effect. A study revealed that female patients and patients from ethnic minorities often choose complementary and alternative medicine (CAM) as the first step in treating depression.¹⁴ This skepticism refers to the trend of using CAM. One type of CAM approach includes natural products like dietary supplements (vitamins, minerals, and probiotics).¹⁵

Dietary supplements are orally consumed products, such as vitamins, herbs, minerals, amino acids, enzymes, metabolites, probiotics, and other substances for supplementing typical diets.¹⁶ Several dietary supplements have also been commonly used for reducing depression symptoms. For example, Kazemi et al¹⁷ explained that dietary supplementation, such as prebiotic use, significantly decreased the Beck Depression Inventory (BDI) scores compared with the placebo group, after eight weeks of intervention. Other dietary supplementations, such as polyunsaturated fatty acid (PUFA), vitamin D,¹⁸ B12,¹⁹ magnesium, zinc,²⁰ and curcumin,²¹ have also been studied for their efficacy and effects as add-on supplements for depression treatment. In a review conducted by Hoffman et al,¹⁸ vitamin D and PUFA supplementation had complementarily positive effects on depressive symptoms, anxiety, and pain. Therefore, this review explored and summarized clinical study updates on dietary supplements’ types, dosages, and effectiveness to reduce symptoms of depression.

Methods

Search Strategy and Selection Criteria

The search of the PubMed database was conducted in August 2021, using the terms “(dietary supplementation) AND (depression)” on the advanced query box. Afterward, some criteria were put in place to choose relevant articles, including only articles published in English, article types reporting clinical studies or randomized controlled trials, and those with a maximum publication date of 10 years.

The Review Process

Extracted article references were manually searched and screened for relevance. Then, we collected the following information: country of study, type of supplementation, the dosage used, the scale of depression, and results.

Clinical Studies on Dietary Supplementations for Treating Depression

Although we finally identified 221 article records from the advanced search data, 137 articles were excluded because the studies did not focus on depression or the journal had incomplete titles and abstracts. Likewise, 21 articles were excluded due to ineligibility (Figure 1). Therefore, we included 63 articles and further grouped these studies into five broad groups based on the number of supplements used in the research. The five groups were PUFA, vitamin D, probiotics, a combination of vitamins and nutrients, and other supplements.

Figure 1 Literature search results.

Table 1 summarizes the study characteristics of the 63 selected articles. We observed that the most common supplementation used was that of the PUFA group and its combination (n = 17, 26.9%), followed by vitamin D (n = 15, 23.8%), probiotics (n = 8, 12.7%), then combination of vitamins and nutrients (n = 6, 9.5%). Furthermore, most clinical studies were conducted in Iran (41.3%), with adult participants aged above 18 (98.4%). From all studies, the most commonly used scale was the BDI and its respective version (47.6%).

Table 1 Study Characteristics

The Polyunsaturated Fatty Acid (PUFA) Group

This review found that the most commonly used supplementation in treating depression was the PUFA group, which was a combination of Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA). Table 2 shows that from the twelve clinical studies that used PUFA supplementation for depression, eight studies showed positive effects in improving depression symptoms and reducing the scale of depression. However, the other four had no significant impact on the scale of depression, meaning that most of the studies agreed that PUFA was beneficial as a treatment for depression.

Table 2 Effects of Using PUFA Supplements for Treating Depression

From the eight studies that showed PUFA’s beneficial effects on depression, we observed that the range of the total daily dosage of the EPA ranged from 0.7 g to 2 g and DHA was from 0.4 g to 0.8 g. Moreover, the frequency of PUFA supplement intake varied from one to nine times daily, within a 3-week to 4-month administration period. Most studies showed beneficial effects in a total daily dose of PUFA supplementation and a total daily dose of 180 mg of EPA and 120 mg of DHA, with an intake frequency of six times daily. However, the studies with no significant impact used a higher dosage with higher study durations of up to three years. However, we identified one study by McNamara et al²² that stated that PUFA had a beneficial effect on depression, with a total daily dosage that was higher than the other studies, more specifically, at 16.2 grams daily (10.8-g EPA + 5.4 g DHA, divided to 2 tablespoons/day). This dosing was based on a previous study that reported supplementation’s efficacy and safety data in patients with attention deficit hyperactivity disorder. Moreover, only one study of the eight,²³ wherein the subjects were pregnant women at various stages of pregnancy, also showed beneficial effects of PUFA’s supplementation on pregnancy depression. A review conducted by Hsu et al²⁴ also supported this result, which explained that in addition to preventing pregnancy-related depression, sufficient consumption of omega-3 fatty acid supplements such as EPA during pregnancy was important, because they served as the critical building blocks of the fetal brain and retina. They also determine the pregnancy length.

Omega-3 fatty acids are substrates that affect the formation of neurotransmitters and prostaglandins. Therefore, they have extensively functions with regard to the maintenance and regulation of a healthy brain. Furthermore, it has been reported that depression rates can increase with lower levels of membrane-related omega-3 fatty acids.²⁵ The main pathway target of omega-3, which is also linked to the inflammatory hypothesis of depression,²⁶ is the arachidonic acid inflammatory pathway.²⁷ Two possible pathways exist in the reduced synthesis of eicosanoids from arachidonic acid by DHA and EPA, as explained by Wani et al.²⁵ First, they combine with arachidonic acid for amalgamation into membrane-based phospholipids, thereby reducing both cellular and plasma concentrations of arachidonic acid. DHA and EPA, which hinder the release of pro-inflammatory cytokines (interferon-γ, tumor necrosis factor [TNF]-α, interleukin [IL]-1β, IL-2, and IL-6), are determined by the eicosanoid discharge. The other possible way is that of the cyclooxygenase enzyme system. Here, EPA can compete with arachidonic acid to block the pro-inflammatory eicosanoid synthesis from arachidonic acid, prostaglandin E2, and thromboxanes B2²⁵ by inhibiting the action of phospholipase A2, as shown in Figure 2.²⁶ Additionally, Lotrich et al²⁸ reported that the elevated ratio of arachidonic acid to omega-3 fatty acid was linked to depression. The observation from other intervention studies also indicated that administering omega-3 fatty acids can decrease this ratio and improve depressive symptoms.

Figure 2 The proposed mechanism of EPA in inhibiting phospholipase A2 and preventing depression.

Additionally, in the pathophysiology of depression, the upregulation of 5-HT2A/C receptors is proposed to play a significant role. From the previous study, it was observed that for an individual with chronic stage omega-3 fatty acid deficiencies, changes in the concentration of brain fatty acids can result in an altered serotonergic or dopaminergic neurotransmission, increase in 5-HT2,²⁷ and decrease in serotonin and dopamine in the prefrontal cortex,²⁹ thereby indicating the importance of adequate PUFA intake. A few studies we obtained also investigated the efficacy of PUFA combined with other dietary supplements, such as 5-aminolevulinic acid (ALA), curcumin, vitamin E, and vitamin B on depression (Table 3). From the five studies obtained, the overall result was that those combinations showed no significant effect. From these studies, only one study showed beneficial supplement effects on depression, which was the combination of PUFA and vitamin E.³⁰ The study used 1000-mg PUFA with 400 IU vitamin E daily for twelve weeks, with the subjects being women with polycystic ovary syndrome (PCOS). Jamilian et al stated that compared to a single supplementation, combining supplements gave better and more significant treatment results, including improved mental health parameters. Alternatively, the other four studies obtained showed statistically non-significant results with the use of PUFA combined with other supplements in treating depression, thereby proposing that PUFA use during depression conditions was preferred without any supplement combination.

Table 3 Effects of Combined PUFA Supplementations for Treating Depression

Vitamin D

Table 4 shows that nine of the 15 vitamin D studies reported beneficial effects on improving depression symptoms. These studies showed that vitamin D supplementation at 2000 IU/day–50,000 IU/week for eight weeks (two months) to 24 months of supplementation positively affected depression. However, although the exact dosage was used in one study, no significant impact on depression was observed since the study included a dialysis patients. Furthermore, the duration of the study was from eight weeks (2 months) to 24 months of supplementation before a positive result. Two studies were also observed in addition to a single supplementation, which combined vitamin D supplementation with probiotics³¹ and zinc.³² The findings of both studies showed that the combined supplementation had positive effects on depression. Therefore, since probiotics and zinc influence depression, its proposed action mechanism is discussed below. Notably, seven of 15 findings mentioned that vitamin D supplementation had no significant effect on depression, which was attributed to the low intervention impact, compared to efficient treatment standards like antidepressants.³³

Table 4 Effects of Vitamin D Supplementation on Depression

The potential function of vitamin D is to regulate calcium-phosphate homeostasis.³⁴ Its mechanism is through the vitamin D receptor, which affects most physiological systems, including the brain.³⁵ Some studies have mentioned that lower serum levels of 25(OH) D3 were associated with depression.³⁶ Furthermore, depression results from some pathways, including chronic inflammation, formation of serotonin, expression of mitochondrial proteins, Ca²⁺ homeostasis, and antioxidant gene expression,³⁷ which are indirectly related to vitamin D. Chronic inflammation accounts for depression in the presence of inflammatory cytokine expression, which can be reduced with vitamin D supplementation.^38–40

The lack of vitamin D in the serum can also lead to depression through mitochondrial function and serotonin formation pathways. In the serotonin formation pathway, vitamin D fails to induce the serotonin-synthesized gene of tryptophan hydroxylase 2 (TPH-2) while repressing the expression of TPH-1.⁴¹ Its consequence is a decline in plasma tryptophan levels; tryptophan cannot be transferred into the brain. This inhibition results in low serotonin levels in the brain, causing depression.⁴² Additionally, mitochondrial function will be impaired in the presence of low serum vitamin D levels,⁴³ resulting in elevated reactive oxygen species (ROS) and reduced ATP formation, impacting Ca²⁺ and antioxidant gene (GSH) homeostasis. Significant antioxidants in neurons are GSH or glutathione. They are depleted when ROS is high,⁴⁴ resulting in depression. Both the elevation of ROS and glutamate, which leads to higher Ca²⁺ levels, causes a decline in the number and size of GABAergic neurons. This decline accounts for the imbalance in excitatory and inhibitory neurons that leads to depression.³⁷ Studies showed that vitamin D supplementation normalized vitamin D levels in the serum to prevent depression. Figure 3 depicts the proposed vitamin D pathway to prevent depression. Toxic doses of vitamin D are been considered to be >50 × 10³ IU/day⁴⁵ and are detailed in Table 5.

Table 5 Dietary Supplementation Permissible Levels

Figure 3 The proposed vitamin D pathway to prevent depression.

Probiotics

Other supplementations studied for reducing depression are probiotics. Probiotics are live microorganisms that can improve gut health. Lately, they have been used to manage and treat various diseases, one of which is depression.⁴⁶ Table 6 shows eight studies reporting the usage of probiotic supplementation in depression. While five of these studies showed beneficial effects on depression symptoms and measured improvements using a depression scale, the other three showed no significant impact on depression.

Table 6 Effects of Probiotic Supplementation for Treating Depression

The microbe species included in the studies with positive results comprised various bacteria from the genus Lactobacillus (L. acidophilus, L. casei, L. fermentum, L.rhamnosus, and L. bulgaricus) and the genus Bifidobacterium (Bifidobacterium bifidum and Bifidobacterium lactis) with various dosage ranges above 10⁸ CFU in the form of yogurt, capsules, and sachets. The positive effect of using probiotic supplementations in depression was also supported by a meta-analysis conducted by Chao et al.⁴⁷ The study explained that probiotics were adjunct therapies that can improve depressive symptoms in patients diagnosed with depression. Yong et al⁴⁸ explained another advantage of probiotics as an antidepressive treatment. According to his study, although probiotics are primarily safe to be consumed and socially help patients, they are proposed not to receive the negative stigma associated with standard antidepressants.

In studies with negative results, Louzada et al⁴⁹ explained that compared to previous studies wherein probiotics simultaneously had significant effects on depression parameter scores, the negative outcome could be attributed to the characteristics of participants included in their research, which are proposed to not have been clinically diagnosed as depressed. Moreover, other uncontrolled events could have interfered with the study result.⁴⁹ It was also explained by Kazemi et al¹⁷ that probiotics were only beneficial when used as an additive to regular antidepressants as compared to probiotics that were used as primary therapy for depression.¹⁷

Although an in-depth mechanism explaining probiotics’ effect on depression is not fully understood yet,⁴⁶ a possible pathway is connected to the microbiota–gut–brain (MGB) axis in the pathophysiology of depression. The MGB axis allows two-way communication between the gut microbiota and the human brain. Depression is therefore developed when the MGB axis becomes maladaptive, adversely affecting the host physiology, which eventually leads to depression. Hence, probiotics also help alleviate depression by modulating the MGB axis. Nevertheless, a few challenges have been observed in explaining the complete mechanism that contributes to the effectiveness of probiotics in depression, including the heterogeneity of depression and the gut microbiota’s complexity.⁴⁸ However, despite these challenges and the unclear mechanism, increasing evidence supports that probiotics are an excellent alternative for depression treatment, compared to standard antidepressants.

The Combination of Vitamins and Nutrients

Table 7 shows six studies reporting a combination of vitamin and nutrient supplementation in depression. We observed that four studies conducted by Nguyen,⁵⁰ Berens,⁵¹ Oliver-Baxter,⁵² and Harris⁵³ revealed beneficial effects of these classes on depression. Nguyen et al⁵⁰ reported that the intervention of multiple micronutrient and iron-folic acid groups had a significant impact on lowering depression scores during the first and second trimesters of pregnancy compared to folic acid alone (P < 0.05) among women in the highest tertile for CES-D scores. Multiple micronutrients, such as vitamin B12, vitamin D, folates, zinc, and selenium, have been recommended for preventing maternal depression.

Table 7 Effects of Combining Vitamins and Nutrient Supplementation as Depression Treatments

Oliver-Baxter⁵² also reported that the consumption of supplements containing 12 vitamins, minerals, and herbs within eight weeks to have significant results in decreasing depression scores and all pro-inflammatory cytokines levels related to depression, such as IL-1β, IL-5, IL-6, TNF-α, and TNF-β. Significant changes in IL-1, TNF-α, and TNF-β caused supplement effects on TNF-related cytokines that modulated fundamental cellular processes, such as inflammation. Withania somnifera, one of the active ingredients, has shown effects on proinflammatory cytokines that interfere with hypothalamic-pituitary-gonadal axis down-regulation of local inflammatory.⁵² When the hypothalamic-pituitary-adrenal axis is repeatedly activated, interrelated systems produce by-products to compensate for failure in other systems, such as decreased lymphocytes and increased pro-inflammatory activities that resulted in inflammation.⁵⁴ Previous studies have shown that depression is highly associated with increased inflammatory marker levels, such as IL-1 and IL-6.⁵²

Several ingredients in multivitamin supplements can potentially improve symptoms of depression, such as folate, vitamin C, vitamin D, and herbal ingredients (Ginseng and Ginkgo biloba), by oxidative-stress reduction and mood enhancement. Zinc, vitamin D, and α-tocopherol have antioxidant and anti-inflammatory activities linked to the mechanism of increased telomere length of leukocyte DNA.⁵⁵

The findings of another study indicated that a small quantity of lipid-based nutrient supplement (SQ-LNS) containing vitamin, mineral, and essential fatty acids did not affect maternal postpartum depression (PDD),⁵⁶ which was proposed to be a result of the dosage of essential fatty acids (alpha-linolenic acid [ALA] and linoleic acid) in SQ-LNS formulation was insufficient to treat depression.⁵⁶ Results from this study are in concurrence with a meta-analysis study where EPA/DHA supplements with substantially greater dosages (>60%) of high dose EPA (0.2–2.2 gram/day) were found to offer more significant results in treating depression than supplements with a lower dosage (<60%).⁵⁷

Other Supplementations

Table 8 shows other supplementations that significantly reduced depression scores, such as carnitine, coenzyme Q10, nanocurcumin, curcumin, magnesium oxide, melatonin, myo-inositol, sumac (Rhus coriaria L.), vitamin A, vitamin B, folic acid, zinc, and zinc sulfate. However, other supplementations, such as vitamin E, C, and ferrous sulfate, did not offer a significant reduction in the depression score in this study due to many factors, such as the short trial duration, limited sample size in each group, low effective doses, and inadequate measurement at the start and end of the trial.^58,59

Table 8 Effects of Other Supplements in Treating Depression

Furthermore, we observed that carnitine’s effect in lowering depression parameter scores was linked to improved mitochondrial performance, antioxidant effects, increased cholinergic neurotransmission, enhanced protein, and gene expression, which affected brain metabolism, thereby aiding the improvement of neuropsychological function.⁶⁰

Coenzyme Q10, nanocurcumin, and curcumin also had neuroprotective properties, including antioxidant and anti-inflammatory activities. Previously, several studies reported that depression was associated with higher TNF-α levels in individuals with depression than in healthy controls. Therefore, these supplements effectively protect brain cells and neurons from significant neurotoxic damage and lower pro-inflammatory cytokine levels (TNF-α and IL-1β), thereby reducing the overproduction of circulating TNF-α and IL-1β caused by lipopolysaccharides.⁶¹ These regulatory effects would help develop depression treatments in the future. Additionally, the studies showed that curcumin and nanocurcumin protected the brain from oxidative stress and regulated serotonin and dopamine release.^62,63 The low oral bioavailability of curcumin in humans is the cause for low levels of curcumin in the plasma and insufficient pharmacological effects.⁶² Thus, many formulations, such as nanoparticles, liposomes, micelles, and phospholipid complexes, have been developed to address this issue and improve curcumin bioavailability. Nanocurcumin is more potential than curcumin in suppressing nuclear factor B and has a higher cellular absorption rate, offering better efficacy at the pharmacological level as compared to curcumin.^62,64 Previous studies have reported that different curcumin formulae administered result in effects of different magnitudes at the behavioral, electrophysiological, and molecular levels in depression. Therefore, future clinical trials on the effects of different curcumin formulations on depression are essential, to evaluate the potential difference in efficacy on depression.^65–67

Rajizadeh et al⁶⁸ investigated the consumption of 500 mg magnesium oxide daily for eight weeks in people with depression and hypomagnesemia. They observed that magnesium oxide improved depression by reducing BDI scores. Although the advised dose for treating depression ranged from 125 mg to 450 mg based on the previous study, the duration of therapeutic supplementation ranged from 7 to 20 months. Based on these findings, magnesium was proposed to be essential for improving synaptic functions, particularly in the hippocampal neurons of the brain. In addition to its role in blocking N-methyl-D- aspartate (NMDA) channels, magnesium also has an excitatory influence on the production of the brain-derived neurotrophic factor (BDNF) involved in brain function and neuron maintenance.⁶⁹ Additionally, magnesium influences the production of cyclic adenosine monophosphate response element-binding proteins that control genes related to brain function, particularly those involved in dopamine synthesis. Thus, magnesium can help alleviate depression.⁶⁸

Melatonin also has a similar mechanism in reducing depression. As observed, melatonin exerts its neuroprotective properties by controlling glutamate’s NMDA-mediated excitotoxic effects, such as through decreased BDNF signaling and necrosis in cells.⁷⁰ Furthermore, melatonin regulates dopamine signaling, which is a precursor of noradrenaline.

MDD has been linked to a decline in monoaminergic neurotransmitters, such as noradrenaline, dopamine, and serotonin.⁷¹ Jamalian et al⁷² observed that myo-inositol (2 g) with 200 ug folate twice a day compared to the metformin group significantly improved BDI and DASS scores in women with polycystic ovary syndrome (PCOS) after 12 weeks of supplementation. Furthermore, myo-inositol lowered the oxidation of thiol groups that prevented the progressive rise of oxidative stress in women with PCOS.

Likewise, Hariri et al⁷³ investigated the effects of sumac (Rhus coriaria L.) supplementation with a total dose of three grams daily in obese women. Although BDI scores reduced significantly in both groups, no significant difference compared with the placebo was observed. Sumac contains gallotannins that have anti-inflammatory activities through their ability to scavenge ROS and suppress inflammatory mediators (COX-2) linked with depression.^74,75

Some vitamin supplementations also help in depression treatment, such as vitamins A and B. Bitarafan et al,⁷⁶ reported that consuming a vitamin A (retinyl palmitate) dose of 2500 IU daily within six months continued by 10.000 IU per day for another six months, significantly improved depression scales in patients with multiple sclerosis. These patients had immune dysfunction and psychosocial stressors that can cause depression.⁷⁶ Therefore, vitamin A influences anti-inflammatory effects by suppressing the growth of inflammatory T-helper cells and lowering the gene expression of inflammatory cytokines.⁷⁷ This modulation can help reduce depression symptoms in patients with MS can be reduced. In contrast, vitamin B, such as B12, folic acid, and B6, also improves depression symptoms. It has been reported that combining vitamin B12 and folic acid lowered homocysteine levels, thereby lowering harmful effects and enhancing the efficacy of antidepressant treatments. In the brain, vitamin B12-dependent methylation influences neurological symptoms and disorders. Thus, vitamin B deficiency can increase homocysteine levels, resulting in increased oxidative stress that can cause depression.⁷⁸

Furthermore, Solati et al⁷⁹ reported that 30 mg of zinc daily in obese women for 12 weeks improved depression scores by increasing BDNF levels. Thus, zinc had a similar mechanism to antidepressants and other supplementations. In turn, the rise of BDNF levels in the hippocampus triggered therapeutic effects in depressed patients. Likewise, Ranjbar et al⁸⁰ investigated the consumption of 25 mg zinc sulfate daily in addition to antidepressants (SSRI citalopram or fluoxetine). As observed, depression scores were significantly different compared to the control group. Zinc also mediated antidepressant effects through other pathways, such as zinc antagonism of the NMDA receptor.⁸⁰ Zinc supplementation results in its storage in the synaptic vesicles of glutamatergic neurons and following neuronal activity that can be transferred into the synaptic cleft, inhibiting glutamate receptors like NMDA is observed.⁸¹

Alternatively, the study by Mazloom reported that although the effect of vitamins C and E did not have significant results on depression levels compared with the placebo in patients with diabetes type-2, vitamin C caused a substantial change in anxiety levels.⁵⁸ This change was proposed to be caused by the short duration of treatment and inadequate doses of vitamin C and E. However, Amr et al⁸² reported that vitamin C supplementation of 500 mg twice a day with fluoxetine (SSRI antidepressant) of 10 mg per day, administered orally in pediatric patients with MDDs, led to a significant reduction in depressive symptoms compared to the group given fluoxetine alone. This finding shows that vitamin C can be an adjunctive therapy for antidepressant drugs. Furthermore, vitamin C offers neuroprotective properties as an additional protection from oxidative free radicals that can cause brain damage and result in depression.⁸³ Similarly, a previous study observed that vitamin C modulated dopamine and glutamate-mediated neurotransmission as a neuromodulator in the brain. Moreover, the complicated connection of vitamin C with the dopaminergic pathway can be another potential mechanism of action, accounting for its efficacy in treating depression.⁸⁴

Implications and Future Directions

Given the positive results of the dietary supplements in reducing depressive symptoms, we suggest that people with depression consult with a specialist before selecting the type of supplementation. The lower and upper permissible levels of consumption of these supplementations also need to be considered (Table 5). Further studies focusing on substances that showed no positive results, with more carefully selected groups, doses, and combinations are needed to provide a more comprehensive and up-to-date overview of existing supplementations to reduce depressive symptoms.

Conclusion

Based on this study, we observed that the most common supplementation used in clinical studies for depression treatment was the PUFA group and its combination (n = 17, 26.98%), followed by vitamin D (n = 15, 23.81%), then probiotics (n = 8, 12.7%). The total daily dosage of PUFA showed its beneficial effect with 0.7–2 g EPA and 0.4–0.8 g DHA daily for three weeks to 4 months. Furthermore, its positive effect was 2000 IU/day–50,000 IU/week vitamin D for eight weeks to 24 months of supplementation. We also observed that microbes from the genus Lactobacillus and Bifidobacterium with various dosage ranges above 10⁸ CFU in yogurt, capsule, and sachets in the probiotic group showed beneficial adjunctive therapy effects in treating depression. The depression scale was therefore valuable to assess the effect of an intervention on depression. Nevertheless, we propose that PUFA, vitamin D, and probiotics be considered beneficial dietary supplementations in depression treatment and management.