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Vitamin deficiencies and mental health: how are they linked? Identifying and correcting deficiencies can improve brain metabolism and psychopathology.

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 (for a Figure that illustrates the methylation cycle, see this article at CurrentPsychiatry.com). Fat-soluble vitamins A, D, and E play important roles in genetic transcription, antioxidant recycling, and inflammatory regulation in the brain.

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) page 38-39) and 3 fat-soluble vitamins (A, D, and E; Table 2, (1) page 40-41) in brain metabolism and psychiatri.c 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.


Table 1

Water-soluble vitamins: Deficiency, insufficiency, symptoms,
and dietary sources

Deficiency      Insufficiency   Symptoms       At-risk
                                               patients
B1 (thiamine): Glycolysis, tricarboxylic acid cycle

Rare; 7% in     5% total, 12%   Wernicke -     Older adults,
heart failure   of older        Korsakoff      malabsorptive
patients        women           syndrome,      conditions,
                                memory         heavy alcohol
                                impairment,    use Those with
                                confusion,     diabetes are at
                                lack of        risk because of
                                coordination,  increased
                                paralysis      clearance

B2 (riboflavin): FMN, FAD cofactors in glycolysis and
oxidative pathways. B6, folate, and glutathione

synthesis
10% to 27% of   <3%; 95% of     Fatigue,       Older adults,
older adults    adolescent      cracked lips,  low intake of
                girls           sore throat,   animal and dairy
                (measured by    bloodshot      products, heavy
                EGRAC)          eyes           alcohol use

B6 (pyridoxal): Methylation cycle

11% to 24%      14% total, 26%  Dermatitis,    Older adults,
(<5ng/ml_);     of adults       glossitis,     women who use
38% of heart                    convulsions,   oral
failure                         migraine,      contraceptives,
patients                        chronic pain,  alcoholism. 33%
                                depression     to 49% of women
                                               age > 51 have
                                               inadequate
                                               intake
B9 (folate): Methylation cycle

0.5% total; up  16% of adults,  Loss of        Depression,
to 50% of       19% of          appetite,      pregnancy and
depressed       adolescent      weight loss,   lactation,
patients        girls           weakness,      alcoholism,
                                heart          dialysis, liver
                                palpitations,  disease.
                                behavioral     Deficiency
                                disorders      during pregnancy
                                               is linked to
                                               neural tube
                                               defects
B12 (cobalamin): Methylation cycle (cofactor methionine
synthase)

10% to 15% of   < 3% to 9%      Depression,    Vegetarian or
older adults                    irritability,  vegan diet
                                anemia,        achlorhydria,
                                fatigue,       older adults.
                                shortness of   Deficiency more
                                breath, high   often due to
                                blood          poor absorption
                                pressure       than low
                                               consumption
C (ascorbic acid): Antioxidant


7.1%            31%             Scurvy,        Smokers, infants
                                fatigue,       fed boiled or
                                anemia, joint  evaporated milk,
                                pain,          limited dietary
                                petechia.      variation,
                                Symptoms       patients with
                                develop after  malabsorption,
                                1 to 3 months  chronic
                                of no dietary  illnesses
                                intake

Deficiency      Dietary
                sources

B1 (thiamine): Glycolysis, tricarboxylic acid cycle

Rare; 7% in     Pork, fish,
heart failure   beans,
patients        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   Dairy, meat
older adults    and fish,
                eggs,
                mushrooms,
                almonds,
                leafy
                greens, and
                legumes

B6 (pyridoxal): Methylation cycle

11% to 24%      Bananas,
(<5ng/ml_);     beans,
38% of heart    potatoes,
failure         navy beans,
patients        salmon,
                steak, and
                whole
                grains


B9 (folate): Methylation cycle

0.5% total; up  Leafy green
to 50% of       vegetables,
depressed       fruits,
patients        dried beans,
                and peas

B12 (cobalamin): Methylation cycle (cofactor
methionine synthase)

10% to 15% of   Meat,
older adults    eafood,
                eggs, and
                dairy

C (ascorbic acid): Antioxidant

7.1%            Citrus
                fruits,
                tomatoes and
                tomato
                juice, and
                potatoes

Table 2

Fat-soluble vitamins: Deficiency, insufficiency, symptoms,
and dietary sources

Deficiency          Insufficiency  Symptoms       At-risk
                                                  patients
A (retinol): Transcription regulation, vision

<5% of U.S.         44%            Blindness,     Pregnant women,
population                         decreased      individuals
                                   immunity,      with strict
                                   corneal and    dietary
                                   retinal        restrictions,
                                   damage         heavy alcohol
                                                  use, chronic
                                                  diarrhea, fat
                                                  malabsorptive
                                                  conditions

D (cholecalciferol): Hormone, transcriptional regulation


[greater than or    69%            Rickets,       Breast-fed
equal to] 50%, 90%                 osteoporosis,  infants, older
of adults age >50                  muscle         adults, limited
                                   twitching      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%
E (tocopherols and tocotrienols): Antioxidant, PUFA protectant, gene

regulation
Rare                93%            Anemia,        Malabsorptive
                                   neuropathy,    conditions,
                                   myopathy,      HIV.
                                   abnormal eye   depression
                                   movements,
                                   weakness,
                                   retinal
                                   damage

Deficiency          Dietary
                    sources

A (retinol): Transcription regulation, vision

<5% of U.S.         Beef liver,
population          dairy
                    products.
                    Convertible
                    beta -
                    carotene
                    sources:
                    sweet
                    potatoes,
                    carrots,
                    spinach,
                    butternut
                    squash,
                    greens,
                    broccoli,
                    cantaloupe

D (cholecalciferol): Hormone, transcriptional regulation

[greater than or    Fatty fish
equal to] 50%, 90%  and fish
of adults age >50   liver oils,
                    sun-dried
                    mushrooms

E (tocopherols and tocotrienols): Antioxidant, PUFA
protectant, gene regulation

Rare                Sunflower,
                    wheat germ,
                    and
                    safflower
                    oils; meats;
                    fish; dairy;
                    green
                    vegetables


Water-soluble vitamins

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 anticoddant. (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 patients (7) 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 docosa-hexaenoic acid. (15)

Dietary folate must be converted to L-methylfolate for use in the brain. Patients with a methylenetetrahydrofolate reducreductase (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)

Leafy greens and legumes such as lentils are top dietary sources of folate; supplemental folic acid has been linked to an increased risk of cancer and overall mortality. (19), (20)

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 patients (11) 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 [greater than or equal to]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.

Fat-soluble vitamins

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.

Although vitamin D is known for its role in bone growth and mineralization, (31) increasing evidence reveals vitamin D's role in brain function and development. (32) Both glial and neuronal cells possess vitamin D receptors in the hippocampus, prefrontal cortex, hypothalamus, thalamus, and substantia nigra--all regions theorized to be linked to depression pathophysiology. (33) A review of the association of vitamin D deficiency and psychiatric illnesses will be published in a future issue of CURRENT PSYCHIATRY.

Vitamin D exists in food as either D2 or D3, from plant and animal sources, respectively. Concentrated sources include oily fish, sun-dried or "UVB-irradiated" mushrooms, and milk.

Vitamin E. There are 8 isoforms of vitamin E--4 tocopherols and 4 tocotrienols--that function as fat-soluble antioxidants and also promote innate antioxidant enzymes. Because vitamin E protects neuronal membranes from oxidation, low levels may affect the brain via increased inflammation. Alpha-tocopherol is the most common form of vitamin E in humans, but emerging evidence suggests tocotrienols mediate disease by modifying transcription factors in the brain, such as glutathione reductase, superoxide dismutase, and nuclear factor-kappaB. (34) Low plasma vitamin E levels are found in depressed patients, although some data suggest this may be caused by factors other than dietary intake. (35) Low vitamin status has been found in up to 70% of older adults. (36) Although deficiency is rare, most of the U.S. population (93%) has inadequate dietary intake of vitamin E. (1) The reasons for this discrepancy are unclear. Foods rich in vitamin E include almonds, sunflower seeds, leafy greens, and wheat germ.

Recommendations

Patients with depression, alcohol abuse, eating disorders, obsessive-compulsive disorder, or schizophrenia may neglect to care for themselves or adopt particular eating patterns. Deficiencies are more common among geriatric patients and those who are medically ill. Because dietary patterns are linked to the risk of psychiatric disorders, nutritional inquiry often identifies multiple modifiable risk factors, such as folate, vitamin B12, and vitamin D intake. (37), (38) Nutritional counseling offers clinicians an intervention with minimal side effect risks and the opportunity to modify a behavior that patients engage in 3 times a day.

Psychiatrists should assess patients' dietary patterns and vitamin status, particularly older adults and those with:

* lower socioeconomic status or food insecurity

* a history of treatment resistance

* restrictive dietary patterns such as veganism

* alcohol abuse.

On initial assessment, test or obtain from other health care providers your patient's blood levels of folate and vitamins D and B12. In some patients, assessing B2 and B6 levels may provide etiological guidance regarding onset of psychiatric symptoms or failure to respond to pharmacologic treatment. Because treating vitamin deficiencies often includes using supplements, evaluate recent reviews of specific deficiencies and consider consulting with the patient's primary care provider.

Conduct a simple assessment of dietary patterns by asking patients about a typical breakfast, lunch, and dinner, their favorite snacks and foods, and specific dietary habits or restrictions (eg, not consuming seafood, dairy, meat, etc.). Rudimentary nutritional recommendations can be effective in changing a patient's eating habits, particularly when provided by a physician. Encourage patients to eat nutrient-dense foods such as leafy greens, beans and legumes, seafood, whole grains, and a variety of vegetables and fruits. For more complex patients, consult with a clinical nutritionist.

Clinical Point

Although rare, severe B1 deficiency can lead to beriberi, Wernicke's encephalopathy, and Korsakoff's psychosis

See this article at

CurrentPsychiatry.com

for a figure that illustrates

the methylation cycle

Clinical Point

Marginal B2 levels

are more prevalent

in depressed

patients, possibly

because of B2's

role in glutathione f

unction

Discuss this article at

www.facebook.com/

CurrentPsychiatry

Clinical Point

B12 deficiency can cause depression, irritability, agitation, and psychosis and can compromise antidepressant response

Clinical Point

Increasing evidence suggests vitamin D plays a role in brain function and development

Clinical Pont

Patients with certain psychiatric disorders, such as depression or psychosis, may adopt eating patterns that lead to vitamin deficiencies

Even rudimentary nutritional recommendations can effectively change patients' eating habits

RELATED ARTICLE: Related Resources

* Institute of Medicine. Dietary Reference Intakes: Recommended intakes for individuals. www.iom.edu/Activities/Nutrition/SummaryDRIs/--/media/Files/Activity9/020Files/Nutrition/DRIs/5_Summary[degrees]/020Table%20Tables%201-4.pdf.

* The Farmacy: Vitamins. http://drewramseymd.com/index.php/resources/farmacy/category/vitamins.

* Office of Dietary Supplements. National Institutes of Health. Dietary supplements fact sheets. http://ods.od.nih.gov/factsheets/list-all.

* Oregon State University. Linus Pauling Institute. Micronutrient information center. http://lpi.oregonstate.edu/infocenter/vitamins.html.

Drug Brand Names

lsotretinoin Accutane

L-methylfolate Deplin

Omeprazole Prilosec

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Bottom Line

Vitamin deficiencies and dietary insufficiency are common, modifiable risk factors that can prevent optimal outcomes in psychiatric practice. Assess patients' baseline vitamin levels and conduct a dietary assessment. Encouraging patients to eat a nutrient-rich diet may prevent psychopathology and increase treatment effectiveness.

Clinical Point

References

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Drew Ramsey, MD

Assistant Clinical Professor of Psychiatry Columbia University College of Physicians and Surgeons

Philip R. Muskin, MD

Professor of Clinical Psychiatry Columbia University College of Physicians and Surgeons

Chief, Consultation-Liaison Psychiatry NY-Presbyterian Hospital, Columbia Campus New York, NY
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Date:Jan 1, 2013
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