Vitamin deficiencies and mental health: How are they linked?
Identifying and correcting deficiencies can improve brain metabolism and psychopathology
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Patients today often are overfed but undernourished. A growing body of literature links dietary choices to brain health and the risk of psychiatric illness. Vitamin deficiencies can affect psychiatric patients in several ways:
- deficiencies may play a causative role in mental illness and exacerbate symptoms
- psychiatric symptoms can result in poor nutrition
- vitamin insufficiency—defined as subclinical deficiency—may compromise patient recovery.
Additionally, genetic differences may compromise vitamin and essential nutrient pathways.
Vitamins are dietary components other than carbohydrates, fats, minerals, and proteins that are necessary for life. B vitamins are required for proper functioning of the methylation cycle, monoamine production, DNA synthesis, and maintenance of phospholipids such as myelin (Figure). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.
Figure: The methylation cycle
Vitamins B2, B6, B9, and B12 directly impact the functioning of the methylation cycle. Deficiencies pertain to brain function, as neurotransmitters, myelin, and active glutathione are dependent on one-carbon metabolism
Illustration: Mala Nimalasuriya with permission from DrewRamseyMD.com
To help clinicians recognize and treat vitamin deficiencies among psychiatric patients, this article reviews the role of the 6 essential water-soluble vitamins (B1, B2, B6, B9, B12, and C; Table 1,1) and 3 fat-soluble vitamins (A, D, and E; Table 2,1) in brain metabolism and psychiatric pathology. Because numerous sources address using supplements to treat vitamin deficiencies, this article emphasizes food sources, which for many patients are adequate to sustain nutrient status.
Water-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources
B1 (thiamine): Glycolysis, tricarboxylic acid cycle
Rare; 7% in heart failure patients
5% total, 12% of older women
Wernicke-Korsakoff syndrome, memory impairment, confusion, lack of coordination, paralysis
Older adults, malabsorptive conditions, heavy alcohol use. Those with diabetes are at risk because of increased clearance
Pork, fish, beans, lentils, nuts, rice, and wheat germ. Raw fish, tea, and betel nuts impair absorption
B2 (riboflavin): FMN, FAD cofactors in glycolysis and oxidative pathways. B6, folate, and glutathione synthesis
10% to 27% of older adults
<3%; 95% of adolescent girls (measured by EGRAC)
Fatigue, cracked lips, sore throat, bloodshot eyes
Older adults, low intake of animal and dairy products, heavy alcohol use
Dairy, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes
B6 (pyridoxal): Methylation cycle
11% to 24% (<5 ng/mL); 38% of heart failure patients
14% total, 26% of adults
Dermatitis, glossitis, convulsions, migraine, chronic pain, depression
Older adults, women who use oral contraceptives, alcoholism. 33% to 49% of women age >51 have inadequate intake
Bananas, beans, potatoes, navy beans, salmon, steak, and whole grains
B9 (folate): Methylation cycle
0.5% total; up to 50% of depressed patients
16% of adults, 19% of adolescent girls
Loss of appetite, weight loss, weakness, heart palpitations, behavioral disorders
Depression, pregnancy and lactation, alcoholism, dialysis, liver disease. Deficiency during pregnancy is linked to neural tube defects
Leafy green vegetables, fruits, dried beans, and peas
B12 (cobalamin): Methylation cycle (cofactor methionine synthase)
10% to 15% of older adults
<3% to 9%
Depression, irritability, anemia, fatigue, shortness of breath, high blood pressure
Vegetarian or vegan diet, achlorhydria, older adults. Deficiency more often due to poor absorption than low consumption
Meat, seafood, eggs, and dairy
C (ascorbic acid): Antioxidant
Scurvy, fatigue, anemia, joint pain, petechia. Symptoms develop after 1 to 3 months of no dietary intake
Smokers, infants fed boiled or evaporated milk, limited dietary variation, patients with malabsorption, chronic illnesses
Citrus fruits, tomatoes and tomato juice, and potatoes
EGRAC: erythrocyte glutathione reductase activation coefficient; FAD: flavin adenine dinucleotide; FMN: flavin mononucleotide
Fat-soluble vitamins: Deficiency, insufficiency, symptoms, and dietary sources
A (retinol): Transcription regulation, vision
<5% of U.S. population
Blindness, decreased immunity, corneal and retinal damage
Pregnant women, individuals with strict dietary restrictions, heavy alcohol use, chronic diarrhea, fat malabsorptive conditions
Beef liver, dairy products. Convertible beta-carotene sources: sweet potatoes, carrots, spinach, butternut squash, greens, broccoli, cantaloupe
D (cholecalciferol): Hormone, transcriptional regulation
≥50%, 90% of adults age >50
Rickets, osteoporosis, muscle twitching
Breast-fed infants, older adults, limited sun exposure, pigmented skin, fat malabsorption, obesity. Older adults have an impaired ability to make vitamin D from the sun. SPF 15 reduces production by 99%
Fatty fish and fish liver oils, sun-dried mushrooms
E (tocopherols and tocotrienols): Antioxidant, PUFA protectant, gene regulation
Anemia, neuropathy, myopathy, abnormal eye movements, weakness, retinal damage
Malabsorptive conditions, HIV, depression
Sunflower, wheat germ, and safflower oils; meats; fish; dairy; green vegetables
HIV: human immunodeficiency virus; PUFA: polyunsaturated fatty acids; SPF: sun protection factor
Vitamin B1 (thiamine) is essential for glucose metabolism. Pregnancy, lactation, and fever increase the need for thiamine, and tea, coffee, and shellfish can impair its absorption. Although rare, severe B1 deficiency can lead to beriberi, Wernicke’s encephalopathy (confusion, ataxia, nystagmus), and Korsakoff’s psychosis (confabulation, lack of insight, retrograde and anterograde amnesia, and apathy). Confusion and disorientation stem from the brain’s inability to oxidize glucose for energy because B1 is a critical cofactor in glycolysis and the tricarboxylic acid cycle. Deficiency leads to an increase in reactive oxygen species, proinflammatory cytokines, and blood-brain barrier dysfunction.2 Wernicke’s encephalopathy is most frequently encountered in patients with chronic alcoholism, diabetes, or eating disorders, and after bariatric surgery.3 Iatrogenic Wernicke’s encephalopathy may occur when depleted patients receive IV saline with dextrose without receiving thiamine. Top dietary sources of B1 include pork, fish, beans, lentils, nuts, rice, and wheat germ.
Vitamin B2 (riboflavin) is essential for oxidative pathways, monoamine synthesis, and the methylation cycle. B2 is needed to create the essential flavoprotein coenzymes for synthesis of L-methylfolate—the active form of folate—and for proper utilization of B6. Deficiency can occur after 4 months of inadequate intake.
Although generally B2 deficiency is rare, surveys in the United States have found that 10% to 27% of older adults (age ≥65) are deficient.4 Low intake of dairy products and meat and chronic, excessive alcohol intake are associated with deficiency. Marginal B2 levels are more prevalent in depressed patients, possibly because of B2’s role in the function of glutathione, an endogenous antioxidant.5 Top dietary sources of B2 are dairy products, meat and fish, eggs, mushrooms, almonds, leafy greens, and legumes.
Vitamin B6 refers to 3 distinct compounds: pyridoxine, pyridoxal, and pyridoxamine. B6 is essential to glycolysis, the methylation cycle, and recharging glutathione, an innate antioxidant in the brain. Higher levels of vitamin B6 are associated with a lower prevalence of depression in adolescents,6 and low dietary and plasma B6 increases the risk and severity of depression in geriatric patients7 and predicts depression in prospective trials.8 Deficiency is common (24% to 56%) among patients receiving hemodialysis.9 Women who take oral contraceptives are at increased risk of vitamin B6 deficiency.10 Top dietary sources are fish, beef, poultry, potatoes, legumes, and spinach.
Vitamin B9 (folate) is needed for proper one-carbon metabolism and thus requisite in synthesis of serotonin, norepinephrine, dopamine, and DNA and in phospholipid production. Low maternal folate status increases the risk of neural tube defects in newborns. Folate deficiency and insufficiency are common among patients with mood disorders and correlate with illness severity.11 In a study of 2,682 Finnish men, those in the lowest one-third of folate consumption had a 67% increased relative risk of depression.12 A meta-analysis of 11 studies of 15,315 persons found those who had low folate levels had a significant risk of depression.13 Patients without deficiency but with folate levels near the low end of the normal range also report low mood.14 Compared with controls, patients experiencing a first episode of psychosis have lower levels of folate, B12, and docosahexaenoic acid.15
Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism produce a less active form of the enzyme. The TT genotype is associated with major depression and bipolar disorder.16 Clinical trials have shown that several forms of folate can enhance antidepressant treatment.17 Augmentation with L-methylfolate, which bypasses the MTHFR enzyme, can be an effective strategy for treating depression in these patients.18
Vitamin B12 (cobalamin). An essential cofactor in one-carbon metabolism, B12 is needed to produce monoamine neurotransmitters and maintain myelin. Deficiency is found in up to one-third of depressed patients11 and compromises antidepressant response,21 whereas higher vitamin B12 levels are associated with better treatment outcomes.22 B12 deficiency can cause depression, irritability, agitation, psychosis, and obsessive symptoms.23,24 Low B12 levels and elevated homocysteine increase the risk of cognitive decline and Alzheimer’s disease and are linked to a 5-fold increase in the rate of brain atrophy.26
B12 deficiencies may be seen in patients with gastrointestinal illness, older adults with achlorhydria, and vegans and vegetarians, in whom B12 intake can be low. Proton pump inhibitors such as omeprazole interfere with B12 absorption from food.
Psychiatric symptoms of B12 deficiency may present before hematologic findings.23 Folic acid supplementation may mask a B12 deficiency by delaying anemia but will not delay psychiatric symptoms. Ten percent of patients with an insufficiency (low normal levels of 200 to 400 pg/mL) have elevated homocysteine, which increases the risk of psychiatric disorders as well as comorbid illnesses such as cardiovascular disease. Top dietary sources include fish, mollusks (oysters, mussels, and clams), meat, and dairy products.
Vitamin C is vital for the synthesis of monoamines such as serotonin and norepinephrine. Vitamin C’s primary role in the brain is as an antioxidant. As a necessary cofactor, it keeps the copper and iron in metalloenzymes reduced, and also recycles vitamin E. Proper function of the methylation cycle depends on vitamin C, as does collagen synthesis and metabolism of xenobiotics by the liver. It is concentrated in cerebrospinal fluid.
Humans cannot manufacture vitamin C. Although the need for vitamin C (90 mg/d) is thought to be met by diet, studies have found that up to 13.7% of healthy, middle class patients in the United States are depleted.27 Older adults and patients with a poor diet due to drug or alcohol abuse, eating disorders, or affective symptoms are at risk.
Scurvy is caused by vitamin C deficiency and leads to bleeding gums and petechiae. Patients with insufficiency report irritability, loss of appetite, weight loss, and hypochondriasis. Vitamin C intake is significantly lower in older adults (age ≥60) with depression.28 Some research indicates patients with schizophrenia have decreased vitamin C levels and dysfunction of antioxidant defenses.29 Citrus, potatoes, and tomatoes are top dietary sources of vitamin C.
Vitamin A. Although vitamin A activity in the brain is poorly understood, retinol—the active form of vitamin A—is crucial for formation of opsins, which are the basis for vision. Childhood vitamin A deficiency may lead to blindness. Vitamin A also plays an important role in maintaining bone growth, reproduction, cell division, and immune system integrity.30 Animal sources such as beef liver, dairy products, and eggs provide retinol, and plant sources such as carrots, sweet potatoes, and leafy greens provide provitamin A carotenoids that humans convert into retinol.
Deficiency rarely is observed in the United States but remains a common problem for developing nations. In the United States, vitamin A deficiency is most often seen with excessive alcohol use, rigorous dietary restrictions, and gastrointestinal diseases accompanied by poor fat absorption.
Excess vitamin A ingestion may result in bone abnormalities, liver damage, birth defects, and depression. Isotretinoin—a form of vitamin A used to treat severe acne—carries an FDA “black-box” warning for psychiatric adverse effects, including aggression, depression, psychosis, and suicide.
Vitamin D is produced from cholesterol in the epidermis through exposure to sunlight, namely ultraviolet B radiation. After dermal synthesis or ingestion, vitamin D is converted through a series of steps into the active form of vitamin D, calcitriol, which also is known as 25(OH)D3.