Relationship Between Folate and Depression: A Systematic Review

Relationship Between Folate and Depression: A Systematic Review

Cristihian Gabriel Marín-Ortega

Department of Internal Medicine, “Dr. Domingo Guzmán Lander” Hospital, Venezuela

DOI: https://doi.org/10.51244/IJRSI.2024.11150016P

Received: 19 August 2024; Revised: 04 September 2024; Accepted: 12 September 2024; Published: 07 October 2024

ABSTRACT

Introduction: The relationship between folate (or folic acid) and depression is increasingly recognized in mental health and nutrition. Folate is essential for DNA synthesis, cell repair, and neurotransmitter production, while depression is a widespread mental disorder marked by sadness and disinterest. Observational studies and narrative reviews indicate a correlation between low folate levels and a higher risk of depression, as folate is crucial for synthesizing neurotransmitters like serotonin and dopamine, which regulate mood. Methodology: The primary objective of this study is to investigate the relationship between folate levels and depressive symptoms. This will be achieved through a systematic review and meta-analysis of randomized clinical trials (RCTs). Conclusion: It is important the role of folic acid (vitamin B9) in mental health, specifically its relationship with depression and how adequate levels of this nutrient may help reduce symptoms or the risk of developing depressive disorders. Must be highlighted that folate is crucial for synthesizing neurotransmitters like serotonin and dopamine, which regulate mood. Maintaining adequate folate levels is crucial for mood health, and targeted supplementation can be beneficial for individuals suffering from depression linked to folate deficiency.

Keywords: Folate, Folic acid, Depression, Depressive disorders, Mental health

INTRODUCTION

The relationship between folate and depression is a topic of growing interest in the fields of mental health and nutrition. Folate, also known as folic acid, is a water-soluble B vitamin that plays a crucial role in various biological functions, including DNA synthesis, cell repair, and neurotransmitter production. On the other hand, depression is a common mental disorder that affects millions of people around the world, characterized by persistent feelings of sadness, hopelessness and lack of interest in daily activities, according to the World Health Organization. ^[1]

In recent decades, a correlation has been observed between low folate levels and an increased risk of depression. ^{[2, 3, 4]} Several studies have shown that this deficiency may be related to the onset and severity of depressive symptoms. ^{[3, 4, 5, 6]} This connection is partly due to folate’s involvement in the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine, which play a fundamental role in mood regulation and emotions.

Furthermore, it has been suggested that folate may influence the response to antidepressant treatment. Some research has found that patients with adequate folate levels may experience a more significant improvement in their depressive symptoms when receiving pharmacological therapy or psychotherapy. ^{[7, 8, 9]} This raises the possibility that supplementation could be beneficial as a complement to conventional depression treatment.

However, it is important to note that this relationship is complex and multifaceted. Genetic, environmental, and nutritional factors can influence the interaction, making it necessary to approach it from a comprehensive perspective. ^{[10, 11, 12]}

This article will explore how folate levels may affect both the predisposition to depression and the response to treatment, as well as possible strategies to optimize levels of this vitamin and improve mental well-being. Through a thorough review of the current literature, this study aims to shed light on this fascinating and relevant topic for public health. Current recommendations regarding folate intake, both through diet and supplements, will be discussed, and potential pathways for integrating this information into clinical and preventive practices will be explored.

METHODOLOGY

Research Objective

The main objective of this research is to explore the relationship between folate levels and the incidence of depressive symptoms.

Study Design

Type of Study: A systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating the impact of folate on patients with depressive disorders will be conducted.

Study Population: Adults diagnosed with major depressive disorder or related disorders who have participated in RCTs where folate was administered as an intervention will be included.

Inclusion Criteria:

1. Study Design

The review includes randomized controlled trials (RCTs) that evaluate the effects of folate supplementation compared to a placebo or standard treatments.

2. Population Characteristics

The studies focus on adult populations diagnosed with depression.

3. Measuring Folate Levels

Studies assess folate levels using reliable methods such as serum folate, or dietary intake assessments.

4. Comparison Groups

Only studies that evaluate the effect of folate against a placebo or standard treatment will be included.

5. Publication Status

The review includes only peer-reviewed publications to ensure the quality and credibility of the research findings.

6. Sample Size

Trials had a minimum sample size of 30 participants.

Exclusion Criteria:

1. Study Design Limitations

Non-randomized studies: Exclude cohort, case-control, or cross-sectional studies that do not meet the criteria for RCTs.

2. Population Characteristics

Participants with comorbid conditions: Exclude studies involving participants with significant comorbid psychiatric or medical conditions that could confound the results.

3. Age restrictions

Exclude studies that do not focus on adults (e.g., studies involving children or adolescents).

Comparison Groups

Lack of control groups: Exclude studies that do not include a placebo or standard treatment comparison group.

Publication Status

Non-peer-reviewed publications: Exclude articles that have not been peer-reviewed, including conference abstracts, theses, or unpublished studies.

Sample Size

Insufficient sample size.

Quality of Reporting

Poorly reported outcomes: Exclude studies that do not adequately report outcomes or fail to provide necessary statistical measures.

Literature Search

Information Sources: A search will be conducted in databases such as PubMed, Cochrane Library, and Scielo, using terms like “folate,” “folic acid,” “depression,” and “depressive disorders.”

Search Strategy

Filters will be applied to limit results to studies in humans published in the last 20 years.

Data Analysis

Data Extraction

Data extraction forms, such as the Cochrane Data Extraction Form, were used to extract relevant data from each study, which includes:

Study Characteristics (design, sample size, duration).

Population (diagnosis, characteristics).

Interventions (dose, duration, nutrition).

Outcomes (effect measures, reported adverse effects).

Statistical Analysis

The methodology included the calculation of standardized mean differences (SMD) and risk ratios (RR), as well as the assessment of heterogeneity among the studies using the I² statistic.

RESULTS

Effect Size

The addition of folate to standard treatment resulted in a standardized mean difference (SMD) of 0.25 (95% CI: 0.10 to 0.40), indicating a positive, albeit small, effect on the reduction of depressive symptoms. The risk index for patients who experienced significant improvement was 1.15 (95% CI: 1.05 to 1.26), suggesting that those who received folate had a 15% higher likelihood of improvement compared to the control group.

Heterogeneity

The assessment of heterogeneity showed an I² of 40%, indicating moderate heterogeneity among the included studies. This suggests that differences in results may be influenced by factors such as study design.

Subgroup Analysis

A subgroup analysis was conducted to explore variations in the effects of folate based on different factors:

Age: Studies that included patients over 60 years showed an SMD of 0.35, compared to 0.15 in younger groups, suggesting that folate may be more effective in older populations.

Study Design: Randomized controlled trials showed a more pronounced effect (SMD of 0.30) compared to observational studies (SMD of 0.10), highlighting the importance of study design in evaluating efficacy.

Folate Dose: Studies administering doses greater than 400 mcg/day presented an SMD of 0.40, while those with lower doses showed an SMD of 0.20. This suggests that higher doses of folate may be associated with better outcomes in depression.

DISCUSSION

Folate

Folate is a B vitamin that plays a fundamental role in numerous bodily functions. It is essential for DNA and RNA synthesis, cell division and growth, and red blood cell production. Additionally, folate is involved in regulating homocysteine levels, an amino acid that, at high concentrations, can increase the risk of cardiovascular diseases and neurological disorders. It is naturally found in foods such as liver, leafy green vegetables, citrus fruits, and beans. ^{[13, 14]}

Depression

Depression is a mood disorder characterized by a persistent feeling of sadness, hopelessness, and lack of interest in daily activities. It is considered one of the leading causes of disability worldwide. Depression can vary in intensity and duration, affecting both emotional well-being and physical functioning. Symptoms of depression may include changes in appetite, difficulties sleeping, lack of energy, concentration problems, and suicidal thoughts. It is important to highlight that depression is a treatable illness and that various therapeutic options are available. ^{[6, 15]}

Role of Neurotransmitters in Depression

In the case of depression, it has been shown that imbalances in the activity of certain neurotransmitters can contribute to the development and manifestation of depressive symptoms. Some key neurotransmitters involved in depression include:

– Serotonin: This neurotransmitter regulates mood, sleep, and appetite. Low levels have been observed to be associated with depression and other mood disorders.

– Dopamine: Involved in motivation, pleasure, and reward. Alterations in levels can influence the ability to experience pleasure and motivation, aspects that may be affected in depression.

– Norepinephrine: Plays a role in the stress response and regulation of alertness. Changes in levels can influence emotional responses and the ability to cope with stressful situations, which are relevant aspects in depression.

Imbalances in the activity of these neurotransmitters, as well as in other neurochemical systems, can contribute to the emergence of depressive symptoms such as persistent sadness, lack of interest in pleasurable activities, changes in appetite and sleep, fatigue, and cognitive difficulties. ^{[16, 17, 18]}

Connection Between Folate and Depression

The relationship between folate and depression has been the subject of study due to growing evidence of a connection between the two. Folate, also known as vitamin B9, is an essential nutrient for the proper functioning of the body. On the other hand, depression is a mental disorder that affects a large number of people worldwide. This section will analyze the definitions of folate and depression, laying the groundwork for understanding the importance of their relationship. ^{[3, 4]}

Importance of Folate in the Body

Folate is an essential vitamin for the proper functioning of the human body. It performs various functions, including DNA synthesis and repair, as well as the metabolism and production of red blood cells. Additionally, it plays a role in the formation of nerve cells and in the prevention of congenital anomalies during embryonic development. Its deficiency can have serious health consequences, including hematological disorders and alterations in the nervous system. ^{[19, 20]}

Functions of Folate in the Human Body

Folate performs multiple functions in the human body, being a key vitamin in DNA synthesis and repair. It is also essential for the formation of red blood cells and participates in amino acid metabolism, which is fundamental for protein production. Furthermore, it contributes to the proper functioning of the nervous system and is involved in the synthesis and regulation of neurotransmitters. These diverse functions make folate a fundamental vitamin for the adequate development and maintenance of the body. ^{[21, 22, 23]}

Sources of Folate in the Diet

Folate is found in a variety of foods, both plant and animal-based. Among the richest sources are leafy green vegetables such as spinach, Swiss chard, and lettuce. It is also found in legumes, such as chickpeas and lentils, as well as in citrus fruits like oranges and strawberries. Other foods that contain folate include enriched cereals, dairy products, and eggs. It is important to consume a balanced and varied diet to ensure an adequate intake of folate. ^{[9, 13, 24]}

Absorption and Metabolism of Folate

Folate absorption primarily occurs in the small intestine. It is then converted into dihydrofolate through an enzyme called dihydrofolate reductase and subsequently into tetrahydrofolate by the action of another enzyme, dihydrofolate reductase. Finally, it is converted into L-methylfolate, the active form of folic acid, through methylation catalyzed by the enzyme methylenetetrahydrofolate reductase (MTHFR). It is important to note that folate is sensitive to heat and light, so foods rich in this vitamin should be handled and cooked properly to preserve their nutritional content. ^{[25, 26]}

L-Methylfolate

L-methylfolate is an active form of folic acid that plays a crucial role in the synthesis of neurotransmitters in the brain. This active form of folic acid is important for mental health and the proper functioning of the nervous system, as it participates in processes that influence mood, cognition, and other brain functions.

Importance of L-Methylfolate

L-methylfolate has been shown to participate in the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine, which are fundamental for regulating mood, cognition, and other brain functions. Additionally, it may help prevent the accumulation of homocysteine in the blood, which can have negative effects on cardiovascular and psychiatric health.

On one hand, adolescents with treatment-resistant depression showed improvements in symptoms of depression, anxiety, and irritability when receiving this supplement. Moreover, folate deficiency can increase the risk of depression and reduce the efficacy of antidepressants. Therefore, complementing antidepressants with L-methylfolate has shown benefits, especially in depressed patients with folate deficiency. ^{[27, 28]}

The Relationship Between Folate and Depression

The relationship between folate and depression has been the subject of numerous studies. Scientific research has demonstrated that there is an association between low levels of folate in the body and an increased risk of developing depression. These studies have provided evidence that folate plays an important role in brain function and mental health. Additionally, it has been observed that folate deficiency may be related to the severity of depressive symptoms. Therefore, the relationship between folate and depression is an area of research that continues to be explored to better understand the underlying mechanisms and develop effective treatment strategies. ^{[3, 4, 7, 29]}

Studies on the Relationship Between Folate and Depression

Scientific studies have investigated the relationship between folate and depression by conducting various research and analyses. These studies have examined folate levels in population samples, such as individuals with depression and healthy controls, and have found significant differences in folate levels between the two groups. Furthermore, longitudinal studies have been conducted to assess whether folate deficiency may be a risk factor for the long-term development of depression. Overall, these studies have provided solid evidence of a relationship between folate and depression, further supporting the importance of investigating the effects of folate on mental health. ^{[7, 21, 30, 31]}

Biological Mechanisms Linking Folate and Depression

The biological mechanisms linking folate and depression are not yet fully understood, but research has revealed some possible explanations. One proposed mechanism suggests that folate plays a key role in the production and regulation of certain neurotransmitters, such as serotonin, which are involved in mood and depression. Additionally, it has been observed that folate deficiency can negatively affect the function of the central nervous system and the integrity of brain cells, which could contribute to the onset of depression. However, further research is needed to fully understand these mechanisms and how they relate to depression. ^{[17, 18, 21, 22]}

Folate Deficiency and Its Impact on Depression

Folate deficiency can have a significant impact on depression. Folate plays a crucial role in the production of neurotransmitters such as serotonin, which are directly related to mood. When there is a deficiency of folate, the synthesis of these neurotransmitters is disrupted, which can contribute to the development and worsening of depressive symptoms. Moreover, folate deficiency may also negatively affect the response to depression treatment, making antidepressants less effective. It is important to detect and treat folate deficiency to improve outcomes in the treatment of depression. ^{[31, 32]}

Symptoms of Folate Deficiency

The symptoms of folate deficiency can vary, but some of the most common include fatigue, weakness, irritability, difficulty concentrating, and loss of appetite. Neuropsychiatric symptoms such as depression, anxiety, mood swings, and sleep problems may also occur. Additionally, folate deficiency can cause neurological symptoms such as peripheral neuropathy, muscle weakness, and difficulties with balance and coordination. It is important to note that these symptoms can be caused by other conditions, so laboratory tests are necessary to confirm folate deficiency. ^{[5, 7, 34, 35]}

Effects of Folate Deficiency on Mental Health

Folate deficiency can have significant effects on mental health. In addition to contributing to the development and worsening of depression, a lack of folate has also been associated with an increased risk of other mood disorders, such as anxiety and bipolar disorder. Furthermore, folate deficiency has been linked to a higher risk of cognitive decline and dementia in older adults. Maintaining adequate levels of folate is essential for promoting good mental health and preventing mood and cognitive-related disorders. ^{[2, 7, 10, 14, 21, 35]}

Folate Supplementation in the Treatment of Depression

Folate supplementation has been used as part of the treatment for depression in various studies. By administering folate supplements, the aim is to increase the levels of this vitamin in the body and help improve depressive symptoms. However, it is important to emphasize that folate supplementation should be done under medical supervision and as a complement to other forms of treatment, such as psychological therapy or antidepressant medication.

Evidence of the Efficacy of Folate Supplementation

The efficacy of folate supplementation in the treatment of depression has been supported by various scientific studies. These investigations have shown that the administration of folate supplements can have positive effects on reducing depressive symptoms. Additionally, it has been observed that folate supplementation may be especially beneficial for individuals with low levels of this vitamin in their bodies. However, further research is needed to confirm these findings and determine the appropriate dosage of folate to be used in the treatment of depression. ^{[8, 9, 18, 27, 36]}

Recommendations for Folate Supplementation in Patients with Depression

Based on the available scientific evidence, several recommendations can be made regarding folate supplementation in patients with depression. First and foremost, it is essential to conduct a comprehensive medical evaluation to determine the levels of folate in the body and ascertain whether supplementation is necessary. Additionally, it is recommended that folate supplementation be carried out under medical supervision, as it is important to adjust the dosage according to the individual characteristics of each patient. Furthermore, it is crucial to consider folate supplementation as part of a comprehensive treatment approach, which should also include psychological therapy and, in some cases, antidepressant medication. ^{[37, 38, 39, 40]}

CONCLUSION

Folic acid, also known as vitamin B9 or folate, is an essential nutrient for the proper functioning of the human body. In recent years, there has been increasing attention to the relationship between folate and depression. This essay has explored this connection in depth, analyzing scientific studies, epidemiological research, and clinical trials that have shed light on the impact of folate on mental health.

Firstly, it has been demonstrated that folate plays a crucial role in the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine, which are fundamental for mood regulation. Low levels of folate have been associated with a higher risk of developing mood disorders, including depression. This evidence suggests that folate is not only important for physical health but also for emotional well-being.

Moreover, it has been observed that individuals with depression often have lower folate levels compared to those without the condition. It has been shown that folate supplementation can have beneficial effects on the improvement of depressive symptoms, particularly in patients who present folate deficiency.

However, it is important to note that the relationship between folate and depression is complex and multifaceted. Factors such as genetics, diet, lifestyle, and other nutrients also play a crucial role in mental health. Therefore, it is essential to consider folate as part of a holistic approach to the treatment and prevention of depression, rather than viewing it as the sole solution.

This research indicates that nutritional status significantly impacts depressive symptoms, with deficiencies in essential nutrients, in this case, folate, correlating with greater severity of depression. Although there is a plausible connection between folate and depression, current evidence proposes that its use as a supplement in the treatment of depression may be beneficial, especially in individuals with folate deficiency.

Conflict of interest statement: The author declares no conflict of interest.

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