B vitamins, depression, folic acid, mood disorder, omega-3 fatty acids, vitamin B



  1. Truesdell, Delores D. MS, RD, LD/N


Depression is prevalent but perhaps underrecognized and undertreated, especially in older adults. Various nutrition-related diseases such as obesity, cancer, and diabetes exacerbate the odds of developing depression. Individuals use dietary supplements with the belief that these substances will reduce depression symptoms. Research has shown that folic acid reduces symptoms of depression in some individuals, but, if taken in excess, it could mask vitamin B12 deficiency. This article provides some review of the clinical evidence regarding the use of selected dietary supplements available for sale in the United States.


Article Content

DEPRESSION is a serious psychological concern and a widely recognized cofactor interacting with disease to produce increased morbidity and mortality.1 The presence of diabetes doubles the odds of comorbid depressions and is associated with hyperglycemia and an increased risk for diabetic complications.2 Raison and Miller3 reported that depression developed in about 25% of patients with cancer, possibly related to neurohumoral changes induced not only by the tumor but also by the cognitive stressors of being diagnosed with a malignancy, and depression is associated with impaired oral intake and malnutrition. According to a 2005 study of 54- to 65-year-old US adults, nearly 1 of every 5 new cases of disability related to activities of daily living is associated with depression.4 People with depression who are taking antidepressants are 50% more likely to fall than other older people, according to a recent study of older Australians.5 If left untreated, depression may also reduce protective immune responses and increase a person's risk of myocardial infarction and stroke, because cytokines and factors that increase blood clotting are released during depression.6,7


The number of depression diagnoses is increasing along with the diagnosis of obesity. Bjerkeset et al8 reported on a prospective cohort of 74 332 men and women (the HUNT study) and found that body mass index increased the odds ratio (OR) for depression per standard deviation to 1.11 (95% confidence interval [CI] = 1.07-1.15). Compton and associates9 estimated that depression occurred in about 7.06% of people in 2001-2002, which was more than double the rate from 10 years earlier. The diagnosis of depression is based on medical history. Table 1 gives an overview of what to look for psychological and physical symptoms, and several potential causes of depression are listed in Table 2.

Table 2 - Click to enlarge in new windowTable 2. Some widely recognized factors or disorders/diseases that are associated with depression or mood
Table 1 - Click to enlarge in new windowTable 1. Diagnostic criteria for major depression

Treatment of depression depends on the cause and associated risks but usually consists of drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin antagonists, norepinephrine, and dopamine-uptake inhibitors) and supportive care that might include cognitive-behavioral therapy, or both drugs and psychotherapy, and sometimes electroconvulsive therapy. Phototherapy may be used in patients with seasonal depression.6,7,10 Risk factors for depression include gender and age; about 20% to 25% of women and 12% of men will experience a serious depression at least once in their lifetime.7,9 The first time when a person experiences depression usually occurs between the ages of 20 and 50, and people older than 65 years are especially vulnerable.7-9 A family history of mood disorders, loss of a parent before the age of 10 years, substance use disorder, diseases such as cancer and diabetes, childhood history of physical or sexual abuse, use of an oral contraceptive in women, use of gonadotropin stimulants as part of infertility treatment in women, persistent psychosocial stressors such as loss of job, and loss of social support system, or the threat of such a loss are risk factors for depression.7-9


About 50% of primary care patients with depression partially respond to medications, and about 50% of those who respond to this treatment do so after 8 or more weeks.10 Antidepressants are associated with dangerous drug-drug and drug-nutrient interactions, but there are lifestyle choices that may be helpful and have minimal risks. Resistance exercise or a physical activity program tailored to the individual's needs and preferences has been shown to have a marked antidepressant effect.11,12 Bright light (10 000 lux) has been shown to decrease depression in the institutionalized elderly.1 Dietary supplements may be used by individuals with the belief that these substances will reduce its symptoms; it is estimated that between 8% and 57% of psychiatric patients with depression and anxiety seek complementary alternative care or take dietary supplements.13,14 Although associations between homocysteine, folate, and vitamin B12 and depression vary in particular populations, folic acid supplementation is linked to an antidepressant effect.15-27



Commercially available dietary supplements come in several different formulations and vary in cost (Table 3). The challenges in developing a palatable and effective form of supplementation that may be effective for the treatment of depression are lack of research, possible effects with standard medications, potency, doses of active compounds, and route of administration.

Table 3 - Click to enlarge in new windowTable 3. Dose, possible costs, and some adverse effects of selected supplements used or recommended for depression (
Table 3 - Click to enlarge in new windowTable 3. Dose, possible costs, and some adverse effects of selected supplements used or recommended for depression

According to Coppen and Bailey,28 low levels of folate could cause a decreased response to antidepressants in some patients. In their study of 127 patients using fluoxetine 20 mg/d, folate 500 [mu]g/d was given to half the subjects whereas the rest received a placebo.28 In the treatment group, 94% of the women had a good response versus 61% in the fluoxetine/placebo group.28 The findings of Fava and coworkers29 were similar to those of Coppen and Bailey. They not only examined the relationships among levels of folate, vitamin B12, and homocysteine but also correlated it to depressive subtype and response to 20 mg/d of fluoxetine in 213 outpatient patients with depression for 8 weeks. The response to treatment was determined by using the 17-item Hamilton Depression Rating Scale.29 They reported that people with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine.29 However, homocysteine and vitamin B12 levels were not associated with depressive subtype or treatment response.29 In their study of outpatients, Fava and coworkers29 concluded that low folate levels reduced the response to antidepressant treatment, so clinicians should consider a possible folate deficiency when evaluating patients with depression who do not respond to antidepressant treatment.


The exact amount of folic acid to be administered is unknown, but a review of the design and power of large randomized control trials (RCTs) suggests that dietary supplementation with folic acid from 0.5 to 5.0 mg/d typically lowered plasma homocysteine concentrations by as much as 25% to 30% in populations without routine folate fortification of food and by about 10% to 15% when there is such fortification.30 Also, excess folic acid can mask vitamin B12 deficiency. Since January 1, 1998, the United States began to fortify grain products with folic acid. After the mandatory enrichment program was instituted, it has been shown that calculated intakes of folic acid and blood folate levels have increased, especially among older adults.31 In fact, some researchers and clinicians are concerned about the increased serum folate levels among selected populations and have suggested that vitamin B12 might also be added during folate fortification.32 To avoid masking vitamin B12 deficiency, vitamin B12 status should be determined before folic acid is given as monotherapy.


Herbs, monoamine oxidase inhibitors, vitamin B6 supplements, ethanol abuse, proton pump inhibitors, and methotrexate may also interfere with nutrient absorption/status and are potential concerns for some patients with depression.33 St John's wort, for example, can interfere with prescription drugs, specifically with the effectiveness of other antidepressants, such as amitriptyline and selective serotonin reuptake inhibitors, oral contraceptives, cyclosporine, digoxin, theophylline, and warfarin.34,35



Tolmunen et al18 investigated the association between dietary folate and symptoms of depression in 2682 men aged 42 to 60 years from eastern Finland. Depressive symptoms were assessed with an 18-item Depression Scale and participants were grouped into tertiles according to their intake of folate. Those in the lowest third of energy-adjusted folate intake had the higher risk of being depressed (OR = 1.67, 95% CI = 1.19-2.35, P = .003), and this risk remained significant after adjustments for smoking, alcohol use, body mass index, marital status, education, total fat consumption, and socioeconomic status.18 Sachdev et al,19 looking at a random subsample of 412 persons, also found low folate levels in persons aged 60 to 64 years to be associated with increased depressive symptoms, but adjustment for homocysteine reduced the incidence ratio to a marginal level. Godfrey et al23 found 41 (33%) of 123 patients with acute psychiatric disorders (Diagnostic and Statistical Manual of Mental Disorders, Third Edition, diagnosis of major depression or schizophrenia) had borderline or definitive folate deficiency. After receiving methyl folate (15 mg daily for 6 months), plus standard psychotropic treatment, there was improved clinical and social recovery among patients with depression and patients with schizophrenia. Although in a small study sample, Godfrey et al23 found that differences in outcome scores between methyl folate and placebo groups became greater with time.


Gilbody and coworkers21 conducted a systematic review of observational studies, and, based on 11 relevant studies (15 315 participants, 3 case-control studies, 7 population surveys, and 1 cohort study) and pooling, found a significant relationship between folate status and depression (ORpooled unadjusted = 1.55; 95% CI = 1.26-1.91).21 This relationship remained after adjustment for potential confounding (ORpooled adjusted = 1.42; 95% CI = 1.10-1.83).21 Folate levels were also lower in those with depression.21 Taylor and coworkers36 found that folate as an adjunct to other treatments reduced Hamilton Depression Rating Scale scores on average by a further 2.65 points (95% CI = 0.38-4.93). Taylor et al36 suggested that it was unclear whether this was the case both for people with normal folate levels and for those with true folate deficiency.


Williams et al37 reported that folic acid at physiological doses did not appear to improve mood in a study of 23 men and for a short time period of 12 weeks. In addition, a meta-analysis of 12 RCTs that included data on 16 968 participants looked at the effect of folic acid supplementation on risk of cardiovascular diseases. Using a random effects model, they did not find folic acid supplementation helpful among participants with a history of vascular disease.38


One proposed mechanism of action for the beneficial effects of folic acid on depression symptoms is related to the "homocysteine hypothesis of depression."15,16 The idea is that high homocysteine levels cause cerebral vascular disease, which causes depression of mood.17 Folic acid lowers homocysteine levels and in the process protects the integrity of the central nervous system.25,26 Another proposed protective mechanism of action is via the hypomethylation hypothesis, which suggests that folate, vitamin B12, and vitamin B6 have direct effects on the central nervous system through their role in 1-carbon transfers or transmethylation reactions in the brain.27 Lack of folate inhibits the synthesis of methionine, an essential amino acid, and S-adenosylmethionine, a methyl donor, which, in turn, inhibits other methylation reactions important to the brain, including the metabolism of neurotransmitters such as dopamine, norepinephrine, and serotonin.27


Evidence for the neurotoxic effects of homocysteine in the brain comes largely from in vitro studies; specific neurotoxic actions are hyperactivation of N-methyl-aspartate receptors and apoptosis.17 Garcia and Zanibbi17 also stated that vascular actions of homocysteine in the brain include an increase proliferation of smooth muscle cells, platelet aggregation, strokes, and white matter lesions. Gilbody et al21 provided another possible mechanism for the homocysteine hypothesis on the basis of a meta-analysis demonstrating an association between the MTHFR C677T variant and depression among other psychiatric disorders such as schizophrenia and bipolar disorder. Gilbody et al22 reviewed several cases for unipolar depression and the MTHFR C677T polymorphism and found fixed-effects OR for homozygote variants (TT) versus the wild type (CC) was 1.36 (95% CI = 1.11-1.67). Their study was based on a review of 1280 cases and 10 429 controls.22


The impact of vitamin B6 on high homocysteine levels is controversial, but vitamin B6, like folic acid, is known to be another homocysteine remethylation cofactor; it is also a cofactor in the tryptophan-serotonin pathway.17 In a systematic review, Maalouf and Grimley39 found 5 RCTs and 1 intervention study that had no evidence that suggested that any form of vitamin B6 supplementation provided short-term treatment of depression. Havas et al40 examined 140 individuals with symptoms of depression and revealed that a low plasma level of pyridoxal phosphate (but not plasma vitamin B12 or erythrocyte folate or plasma total homocysteine) was significantly associated with the depression score (P = .002). Williams et al,41 studying premenopausal women, found that vitamin B6 supplementation was useful for hormone-related depression.


Vitamin B12 is intimately involved with folic acid metabolism, acting as a cofactor for methionine synthase (Fig 1).16,17 Methionine synthase remethylates homocysteine to methionine by using 5-methyltetrahydrofolate as a methyl donor.17 Vitamin B12 deficiency is prevalent in older adults and increases with age, causing multiple abnormalities including megaloblastic anemia, gastrointestinal changes, peripheral neuropathy, subacute combined degeneration, depression, and cognitive impairment.17 Dimopoulos et al42 suggested that low levels of plasma vitamin B12 and higher levels of plasma homocysteine are related to depression in the elderly. Clement et al,43 studying 73 individuals in 2 dialysis centers by using the Beck Depression Index II and the Folstein Mini-Mini Mental State Examination to assess for depression, found lower serum cobalamin levels in subjects with depression than in subjects without depression undergoing hemodialysis. The Rotterdam Study examined the association between low levels of vitamin B12, folate, and homocysteine and depression in 3884 older adults and reported that older adults with vitamin B12 deficiency were more likely to exhibit depressive symptoms than those without vitamin B12 deficiency.44 For hyperhomocysteinemia and folate deficiency, association with depressive disorders was reduced significantly after controlling for functional disability and cardiovascular diseases.44

Figure 1 - Click to enlarge in new windowFigure 1. Folic acid-vitamin B

For depression, Coppen and Bolander-Gouaille16 suggested that oral doses of both folic acid (800 [mu]g daily) and vitamin B12 (1 mg daily) should be administered to improve treatment outcome. The upper limit for folic acid is 1000 [mu]g daily, but there is no upper limit defined for vitamin B12. If vitamin B6 is found to be a useful adjunct in treatments related to depression, a tolerable upper intake level of vitamin B6 for adults is 100 mg/d (Table 3).



The lack of sun exposure from limited outdoor activity, different housing or clothing habits, and decreased vitamin intake may be secondary to depression, but several researchers believe that poor vitamin D status could also cause depression.45-47 Aloia et al,48 in an RCT with 138 subjects, reported a dose of 95 [mu]g/d (3800 IU) of vitamin D3 necessary for subjects above a 25-hydroxyvitamin D (25(OH)D) threshold of 55 mmol/L and a dose of 125 [mu]g/d (5000 IU) necessary for subjects below a threshold of 55 mmol/L to attain optimal vitamin D status defined as 25(OH)D > 75 nmol/L. Barclay49 reported on a population-based study cohort for the Longitudinal Aging Study Amsterdam. The purpose of this study was to look at the relationship between depression and altered vitamin D and parathyroid hormone (PTH) levels in 1282 community residents aged 65 to 95 years.49 Participants completed a self-reported Center for Epidemiologic Studies Depression Scale and diagnostic interviews. In addition to measuring levels of 25(OH)D and PTH, potentially confounding variables of age, sex, smoking status, body mass index, number of chronic conditions, serum creatinine concentrations, and explanatory variables such as season of data acquisition, level of urbanization, and physical activity levels were assessed.49 Results showed that the severity of depression was significantly associated with decreased serum 25(OH)D levels (P = .03) and increased serum PTH levels (P = .008). The levels of PTH were 5% higher in those with minor depression and 33% higher in those with major depressive disorder (P = .003) than among control subjects. A mean serum 25(OH)D level of 21 +/- 10 ng/mL and a mean serum PTH level of 3.6 +/- 1.7 pg/mL were found. The levels of 25(OH)D were 14% lower in persons with minor depression and 14% lower in persons with major depressive disorder in elderly patients than among control subjects.49 Vitamin D status was insufficient in at least one third (38.8%) of the men and more than half (56.9%) of the women.49 There were limitations to this cohort study, including the observational design and an inability to determine causal relationships; in addition, the prevalence of minor depression in older persons was high at 13%.49 Even with the limitations, this study provides a possible link and addresses a nutrient known to be deficient in many population groups.49



Several recent reports or studies supported the use of omega-3 fatty acid supplements for people with depression and the mechanism is thought to be related to selective uptake by the brain and nervous system, neurotransmitter functions, or cytokine synthesis.50-57 Sontrop and Campbell54 reported that in 4 of 7 double-blind RCTs, depression in patients improved with at least 1 g/d of eicosapentaenoic acid. Akabas and Deckelbaum58 and Hibbeln et al59 reported that eicosapentaenoic acid and docosahexaenoic acid together are better than either of them used alone and omega-3 fatty acids are more likely to be helpful for patients with severe depressive symptoms. Some areas of concern related to research on omega-3 fatty acids and depression include the appropriate dose of omega-3 fatty acids, the length of time required for significant response, and the complex issue of the relationship between eicosapentaenoic acid and docosahexaenoic acid. The Merck Manual suggests that adverse effects from fish oil supplements include a fishy taste, nausea, diarrhea, and risk of bleeding with intakes greater than 3 g/d.60



Nutrition counseling is not usually a part of standard practice for treating depression. Registered dietitians may initially see a patient for weight gain resulting from medications and, on discovering the presence of depressive systems, make a referral to an appropriate healthcare professional. Increased or decreased appetite, inadequate or excessive protein energy intake, inconsistent carbohydrate intake, and involuntary or unintended weight loss are also standard nutritional diagnostic statements important to nutritional assessments and linked to depression or depressive disorders.61 The registered dietitian may also see a cancer patient to help with quality of life, for diabetes management, and for failure to thrive and find a potential risk of B vitamin deficiency particularly in a nursing home setting. According to Garcia and Zanibbi,17 the prevalence of vitamin B12 deficiency among elderly people ranges from 6% to 16%.


The Geriatric Depression Scale and the Beck Depression Inventory II (among other tests) can be used for screening depression in obese patients or older adults; however, there are questions related to the validation of any screening tool for depression. A recent Cochrane review, for example, found that there is substantial evidence that screening for depression has minimal impact on the outcome of depression and some researchers recommend that this screening effort be resisted by clinicians.62 For screening residents in nursing homes, a 2-step approach is often used by nursing. First, a Mini-Mental State Examination is administered to assess cognitive function. Next, those with a score of 15 or more are screened with the Geriatric Depression Scale.


When problems emerge during screening, an explanation should be given to patients and caregivers about the rationale of how supplements may work including upper tolerance limits or any concerns related to a particular dietary supplement. Currently, there is no strong clinical evidence available at this time that demonstrates that any dietary supplement cures depression. Irrespective of depression to target high homocysteine levels, the American Dietetic Association's Evidence Analysis Library suggested that the B vitamins folate, vitamin B6, and vitamin B12 be incorporated into the cardioprotective dietary pattern at the level of the dietary reference intake.63 If an individual has high serum homocysteine levels (usually >13 [mu]mol/L), these B vitamins may lower serum homocysteine by 17% to 34%.


Overall care should be coordinated in the outpatient setting, with a review of pertinent diet-nutrient interactions, provision of a diet, counseling and appropriate literature, referral to useful Web sites (, or support groups. The Dietary Guidelines for Americans are also helpful since they focus on a healthy weight and include recommendations for physical activity.64


Helpful systems for determining whether malnutrition or psychosocial problems exist in elderly clients or patients are the Mini Nutrition Assessment and the Subjective Global Assessment. If a nutrient deficiency is suspected, then imaging studies for vascular diseases and biochemical measures such as hematocrit, white blood cells count, serum urea nitrogen levels, serum secretory protein concentration, total cholesterol levels, lymphocyte count, and serum and erythrocyte folate levels are recommended.15,65 If depression is associated with failure to thrive in the elderly, then laboratory and radiologic evaluations might include a complete blood cells count, chemistry panel, thyroid-stimulating hormone level, urinalysis, and other studies appropriate to the specific individual.66



Depression is something all clinicians should consider, especially with the possibility of disability and multiple treatment-related adverse effects from comorbid conditions, and the potential for drug interactions between antidepressants and dietary supplements. Education and awareness of new research findings are keys to helping patients with depression. Although antidepressants are widely used and effective for depression, they may not stay effective, might increase risk of falls, and thwart attempts to combine diet, exercise, and lifestyle modifications with therapy. Although several studies support folic acid, vitamin D, or omega-3 fatty acid supplementation as having antidepressant roles, controversy still exists and more high-quality, RCTs are needed for efficacy and safety assessment.




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