Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review

Abstract

Depressive disorders pose significant challenges to global public health, necessitating effective prevention and management strategies. Notably, the occurrence of suicide frequently coincides with depressive episodes. Suicide is as a paramount global health concern that demands efficacious preventive strategies. Current psychiatric approaches heavily rely on pharmacological interventions but have had limited success in addressing the global burden of mental health issues. Suboptimal nutrition, with its impact on the neuroendocrine system, has been implicated in the underlying pathology of depressive disorders. Folate, a group of water-soluble compounds, plays a crucial role in various central nervous system functions. Depressed individuals often exhibit low levels of serum and red blood cell folate. Multiple studies and systematic reviews have investigated the efficacy of folic acid and its derivative, L-methylfolate, which can cross the blood–brain barrier, as stand-alone or adjunct therapies for depression. Although findings have been mixed, the available evidence generally supports the use of these compounds in depressed individuals. Recent studies have established links between the one-carbon cycle, folate–homocysteine balance, immune system function, glutamate excitation via NMDA (N-methyl-D-aspartate) receptors, and gut microbiome eubiosis in mood regulation. These findings provide insights into the complex neurobiological mechanisms underlying the effects of folate and related compounds in depression. Through a comprehensive review of the existing literature, this study aims to advance our understanding of the therapeutic potential of folic acid and related compounds in depression treatment. It also seeks to explore their role in addressing suicidal tendencies and shed light on the neurobiological mechanisms involved, leveraging the latest discoveries in depression research.

Serum Vitamin Levels, Cardiovascular Disease Risk Factors, and Their Association with Depression in Korean Women: A Cross-Sectional Study of a Nationally Representative Sample

“…Studies of the association between serum vitamins and depression in Asian subjects are rare [6,7]. Previous studies in Western populations have generally reported that vitamin A levels are positively associated with depression [5,[21][22][23] and that vitamin E and vitamin B9 levels are negatively association with depression [8,10,11,[24][25][26][27][28][29]. Based on the conclusions of previous studies, the content is as follows.…”

Homicide or Happiness: Did Folate Fortification and Public Health Campaigns Influence Homicide Rates and the Great American Crime Decline?

“…Beginning in the early to mid-1980s, there was increased recognition that prenatal folic acid supplementation appeared to cut the risk of neural tube defects [19]; in 1989, the results of a large cohort study (n = 23,491) showed that folic acid supplementation during the first six weeks of pregnancy resulted in neural tube defects at a rate of 0.9 per 100,000 births, compared to 3.5 per 100,000 for women who did not take a multivitamin or folic acid supplement [20]. The results, published in the Journal of the American Medical Association (JAMA), were highly publicized in front page newspaper articles throughout the have been reported to improve depression and other mental disorders [12,13], its role in antisocial behavior and aggression is less often discussed.…”

“…For example, omega-3 fatty acids, or a lack thereof, have been linked to impulsivity, suicide by violent means, and national homicide rates [10]. Although folate, part of the B vitamin family, has long-since been understood to play a critical role in supporting normal central nervous system function [11], and folic acid and other related compounds have been reported to improve depression and other mental disorders [12,13], its role in antisocial behavior and aggression is less often discussed. Here, we suggest that the increased marketing of folic acid supplementation and subsequent food fortification, as a means to reduce neural tube defects, played a part in the relatively sudden and unexpected decrease in homicide rates and other violent crimes in the 1990s.…”

“…Nutrients 2024, 16, x FOR PEER REVIEW 2 of 11 have been reported to improve depression and other mental disorders [12,13], its role in antisocial behavior and aggression is less often discussed.…”

Folate supplementation as a beneficial add‐on treatment in relieving depressive symptoms: A meta‐analysis of meta‐analyses

“…Growing research demonstrated that depression might be linked to folate deficiency. Particularly, studies indicate a link between folate deficiency and an increased risk of depression, more severe depressive symptoms, more prolonged episodes of depression, increased risk of depressive symptom relapse, and poor response to antidepressants (Bender et al., 2017 ; Liwinski & Lang, 2023 ; Martínez‐Cengotitabengoa & González‐Pinto, 2017 ). However, some studies also showed that low‐serum folate levels have been positively associated with depression (Huang et al., 2018 ; Kaner et al., 2015 ; Khalili et al., 2022 ; Lin et al., 2020 ; Seppälä et al., 2013 ), whereas others have found no difference (Gargari et al., 2012 ; Gilbody et al., 2007 ; Kendrick et al., 2008 ).…”