Journal of the Scientific Society

: 2015  |  Volume : 42  |  Issue : 2  |  Page : 59--61

Serum cholesterol and depression: A puzzle never finished

Satish Kumar Budania1, Monika Rathi2, Shalini Singh3, Suresh Yadav4,  
1 Department of Psychiatry, Lala Lajpat Rai Memorial Medical College, Meerut, Uttar Pradesh, India
2 Department of Pathology, Lala Lajpat Rai Memorial Medical College, Meerut, Uttar Pradesh, India
3 Department of Psychiatry, Lady Hardinge Medical College, New Delhi, India
4 Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India

Correspondence Address:
Monika Rathi
228/16, Saket Colony, North Civil Lines,Muzaffar Nagar - 251 001, Uttar Pradesh


Depression is a state of sadness, hopelessness, and discouragement. Various studies have been conducted to uncover the etiological factors involved in depression. Serum folic acid is one such factor. Many researchers have reported an inverse association between serum folic acid and depression. We did an extensive computerized database searches on PubMed, Medline, and EBSCO and found that low serum folic acid are associated with depression, not only in adults, but also in elderly and diabetic patients. Further augmentation of folic acid with antidepressant treatment also improves the treatment outcome in depressed patients. Hence, considering the high benefits to the adverse effects ratio of serum folic acid, its supplementation should be done in DQat riskDQ population whenever possible.

How to cite this article:
Budania SK, Rathi M, Singh S, Yadav S. Serum cholesterol and depression: A puzzle never finished.J Sci Soc 2015;42:59-61

How to cite this URL:
Budania SK, Rathi M, Singh S, Yadav S. Serum cholesterol and depression: A puzzle never finished. J Sci Soc [serial online] 2015 [cited 2020 Sep 23 ];42:59-61
Available from:

Full Text


Depression is a common and treatable psychiatric illness. Various studies have been done to establish a relationship between serum folic acid and depression. Majority of them have reported an association between the two.

Folic acid plays an important role in the synthesis of neurotransmitters, purine, thymidine, nucleotide, DNA, structural components of neurons, by regulating the genomic and nongenomic methylation reactions. [1],[2] The mechanism involved behind this is that folic acid and Vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups in many reactions, including methylation of membrane phospholipids, thereby affecting the membrane properties crucial for neurological functions. [3],[4] Further, SAM also has anti-depressant actions, and it acts by raising brain 5-hydroxytryptamine. [4] Thus, deficiency of folate leads to depression.

Regarding causes of low folate levels, it is also hypothesized that low dietary intake of folate, polymorphism of the genes involved in folate metabolism are responsible for folate deficiency. [5] Interestingly, it is seen that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate) have very low lifetime rates of major depression. [3] Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is overrepresented among depressive subjects.

Increased plasma homocysteine levels act as a marker of both folate and Vitamin B12 deficiency. Hence, a common decrease in serum/red blood cell folate, serum Vitamin B12 and an increase in plasma homocysteine has often been reported in depression. [3]

Folic acid deficiency and Vitamin B12 deficiency have overlapping neuropsychiatric manifestations, which range from cognitive impairment, dementia, depression to the less common manifestations like peripheral neuropathy and combined degeneration of the spinal cord. [2] Studies have also shown that deficiency of folic acid and Vitamin B12 have negative consequences on the brain development in the infants, which leads to a greater risk of depression in adulthood. [6]


We reviewed the literature on computerized databases like PubMed, Medline, and EBSCO, using folic acid, depression, psychiatry as keywords from 2003 to 2014. We also searched the reference lists of the relevant articles in order to include as many relevant studies as possible. We also consulted the experts in this field to take their guidance.

Studies approving association between low serum folate levels and depression

It has been proved that low serum folate levels were found to be associated with fluoxetine resistant major depressive disease. [7] Studies have also proved that low folate level are associated with relapse during the continuation phase of treatment with fluoxetine. [8]

Various other studies have also shown the association between low folate levels and depression. [9],[10],[11],[12],[13],[14],[15],[16],[17] Yaremco et al. did a study on 24 pregnant women with a history of mood disorders. They found that red blood cell folate of these women had an inclination towards low normal range despite the daily use of folic acid supplements. [18] Miyaki et al. also reported a low incidence of depression in patients with normal serum folate levels. [19]

Loria-Kohen et al. did a prospective, clinical trial on the depressive status of 24 patients of eating disorders. They supplemented these patients with 10 mg/day of folic acid. They found a significant improvement in the depressive status of these patients after folate supplementation. [1]

Permoda-Osip et al. treated 20 patients with bipolar depression with ketamine infusion. They found that that the patients whose responded more than 50% on Hamilton depression rating scale had significantly higher levels of Vitamin B12. However, they found no difference with regard to serum folic acid levels and homocysteine levels. [20]

Venkatasubramanian et al. treated 42 depressive female outpatients with 20 mg fluoxetine. They augmented 23 patients with 1.5 mg folic acid/day and 19 patients with 5 mg folic acid/day. They found that augmentation with 5 mg/day folic acid was more beneficial in depressive patients. [21]

Studies disapproving association between low serum folate levels and depression

Aishwarya et al. did a postpartum study on 103 women. They found significant elevations in homocysteine levels in women with postpartum depression, both at 24-48 h as well as 6 weeks after delivery. However, they found no associations between folate and B12 levels. [22]

Walker et al. did a randomized control trial on 909 depressed older adults (60-74 years). They found that neither folic acid plus B12 nor physical activity were effective in reducing depressive symptoms. Instead, mental health literacy had a transient effect on decreasing depressive symptoms. [23] Lukose et al. found that antenatal depressive symptoms in early pregnancy are not associated with folate deficiency. [24] Similar findings were reported in pregnant women by Bodnar et al. [25],[26]

Mazeh et al. also denied the association between folic acid deficiency and psychiatric illness in elderly. [27]

Studies approving the association between low serum folate and depression on special populations

Gosney et al. did a study on older people in nursing homes and residential homes and found that depression was significantly associated with selenium levels in older people, but not with folic acid. [28]

Researchers have reported low folate levels in elderly people of age. [29],[30],[31],[32],[33] Few studies have reported the association between depressive symptoms in pregnancy and folate levels. [34],[35]

Nanri did a study on type 2 diabetic patients and found an inverse association between folic acid levels and depression. [36]


We conclude that not only majority of the studies have proved an association between low serum folate levels and depression, few studies have also suggested that antidepressants augmented with folic acid have better results on treatment outcome. Considering low costs and lesser side-effects of folic acid, folic acid supplements should be given to the depressed patients whenever possible.


We acknowledge Randy A. Sansone, Domenico De Berardis, Stefano Marini, Monica Piersanti, Marilde Cavuto, Giampaolo Perna, Alessandro Valchera, Monica Mazza, Michele Fornaro, Felice Iasevoli, Giovanni Martinotti, and Massimo Di Giannantonio for their guidance. We also acknowledge Engineer Ayush for his technical help.


1Loria-Kohen V, Gómez-Candela C, Palma-Milla S, Amador-Sastre B, Hernanz A, Bermejo LM. A pilot study of folic acid supplementation for improving homocysteine levels, cognitive and depressive status in eating disorders. Nutr Hosp 2013;28:807-15.
2Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol 2014;120:927-43.
3Coppen A, Bolander-Gouaille C. Treatment of depression: Time to consider folic acid and vitamin B12. J Psychopharmacol 2005;19:59-65.
4Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:841-63.
5Nazki FH, Sameer AS, Ganaie BA. Folate: Metabolism, genes, polymorphisms and the associated diseases. Gene 2014;533:11-20.
6Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr Bull 2008;29:S126-31.
7Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: Predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry 2004;65:1090-5.
8Papakostas GI, Petersen T, Mischoulon D, Green CH, Nierenberg AA, Bottiglieri T, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: Predictors of relapse during the continuation phase of pharmacotherapy. J Affect Disord 2013;150: 644-8.
9Nanri A, Hayabuchi H, Ohta M, Sato M, Mishima N, Mizoue T. Serum folate and depressive symptoms among Japanese men and women: A cross-sectional and prospective study. Psychiatry Res 2012;200:349-53.
10Beydoun MA, Shroff MR, Beydoun HA, Zonderman AB. Serum folate, vitamin B-12, and homocysteine and their association with depressive symptoms among U.S. adults. Psychosom Med 2010;72:862-73.
11Farah A. The role of L-methylfolate in depressive disorders. CNS Spectr 2009;14:2-7.
12Dias VV, Brissos S, Cardoso C, Andreazza AC, Kapczinski F. Serum homocysteine levels and cognitive functioning in euthymic bipolar patients. J Affect Disord 2009;113:285-90.
13Obeid R, McCaddon A, Herrmann W. The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med 2007;45:1590-606.
14Clement L, Boylan M, Miller VG, Rockwell M, Allred K. Serum levels of folate and cobalamin are lower in depressed than in nondepressed hemodialysis subjects. J Ren Nutr 2007;17:343-9.
15Lerner V, Kanevsky M, Dwolatzky T, Rouach T, Kamin R, Miodownik C. Vitamin B12 and folate serum levels in newly admitted psychiatric patients. Clin Nutr 2006;25:60-7.
16Sachdev PS, Parslow RA, Lux O, Salonikas C, Wen W, Naidoo D, et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med 2005;35:529-38.
17Permoda-Osip A, Dorszewska J, Skibinska M, Chlopocka-Wozniak M, Rybakowski JK. Hyperhomocysteinemia in bipolar depression: Clinical and biochemical correlates. Neuropsychobiology 2013;68:193-6.
18Yaremco E, Inglis A, Innis SM, Hippman C, Carrion P, Lamers Y, et al. Red blood cell folate levels in pregnant women with a history of mood disorders: A case series. Birth Defects Res A Clin Mol Teratol 2013;97:416-20.
19Miyaki K, Song Y, Taneichi S, Tsutsumi A, Hashimoto H, Kawakami N, et al. Socioeconomic status is significantly associated with the dietary intakes of folate and depression scales in Japanese workers (J-HOPE Study). Nutrients 2013;5:565-78.
20Permoda-Osip A, Dorszewska J, Bartkowska-Sniatkowska A, Chlopocka-Wozniak M, Rybakowski JK. Vitamin B12 level may be related to the efficacy of single ketamine infusion in bipolar depression. Pharmacopsychiatry 2013;46:227-8.
21Venkatasubramanian R, Kumar CN, Pandey RS. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. J Affect Disord 2013;150:644-8.
22Aishwarya S, Rajendiren S, Kattimani S, Dhiman P, Haritha S, Ananthanarayanan PH. Homocysteine and serotonin: Association with postpartum depression. Asian J Psychiatr 2013;6:473-7.
23Walker JG, Mackinnon AJ, Batterham P, Jorm AF, Hickie I, McCarthy A, et al. Mental health literacy, folic acid and vitamin B12, and physical activity for the prevention of depression in older adults: Randomised controlled trial. Br J Psychiatry 2010;197:45-54.
24Lukose A, Ramthal A, Thomas T, Bosch R, Kurpad AV, Duggan C, et al. Nutritional factors associated with antenatal depressive symptoms in the early stage of pregnancy among urban South Indian women. Matern Child Health J 2014;18:161-70.
25Bodnar LM, Wisner KL, Luther JF, Powers RW, Evans RW, Gallaher MJ, et al. An exploratory factor analysis of nutritional biomarkers associated with major depression in pregnancy. Public Health Nutr 2012;15:1078-86.
26Watanabe H, Suganuma N, Hayashi A, Hirowatari Y, Hirowatari T, Ohsawa M. No relation between folate and homocysteine levels and depression in early pregnant women. Biosci Trends 2010;4:344-50.
27Mazeh D, Cholostoy A, Zemishlani C, Barak Y. Elderly psychiatric patients at risk of folic acid deficiency: A case controlled study. Arch Gerontol Geriatr 2005;41:297-302.
28Gosney MA, Hammond MF, Shenkin A, Allsup S. Effect of micronutrient supplementation on mood in nursing home residents. Gerontology 2008;54:292-9.
29Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Yoon JS. Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Br J Psychiatry 2008;192:268-74.
30Ng TP, Aung KC, Feng L, Scherer SC, Yap KB. Homocysteine, folate, vitamin B-12, and physical function in older adults: Cross-sectional findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr 2012;96:1362-8.
31Pan WH, Chang YP, Yeh WT, Guei YS, Lin BF, Wei IL, et al. Co-occurrence of anemia, marginal vitamin B6, and folate status and depressive symptoms in older adults. J Geriatr Psychiatry Neurol 2012;25:170-8.
32Shahar D, Levi M, Kurtz I, Shany S, Zvili I, Mualleme E, et al. Nutritional status in relation to balance and falls in the elderly: A preliminary look at serum folate. Ann Nutr Metab 2009;54:59-66.
33Marengoni A, Cossi S, De Martinis M, Calabrese PA, Orini S, Grassi V. Homocysteine and disability in hospitalized geriatric patients. Metabolism 2004;53:1016-20.
34Van Dijk AE, Van Eijsden M, Stronks K, Gemke RJ, Vrijkotte TG. Maternal depressive symptoms, serum folate status, and pregnancy outcome: Results of the Amsterdam Born Children and their Development study. Am J Obstet Gynecol 2010;203:563.e1-7.
35Fowles ER, Murphey C, Ruiz RJ. Exploring relationships among psychosocial status, dietary quality, and measures of placental development during the first trimester in low-income women. Biol Res Nurs 2011;13:70-9.
36Nanri A. Nutritional epidemiology of type 2 diabetes and depressive symptoms. J Epidemiol 2013;23:243-50.