Depression, folate deficiency

In view of the well-documented inhibition of dihydrofolate reductase by aminopterin (325), methotrexate (326) and related compounds it is generally accepted that this inhibitory effect constitutes the primary metabolic action of folate analogues and results in a block in the conversion of folate and dihydrofolate (DHF) to THF and its derivatives. As a consequence of this block, tissues become deficient in the THF derivatives, and this deficiency has many consequences similar to those resulting from nutritional folate deficiency. The crucial effect, however, is a depression of thymidylate synthesis with a consequent failure in DNA synthesis and arrest of cell division that has lethal results in rapidly proliferating tissues such as intestinal mucosa and bone marrow (B-69MI21604, B-69MI21605). 

Anyone taking diuretics for longer than six months may experience a folate, or folic acid, deficiency. Folic acid plays a part in the health and reproduction of virtually every cell in the body. It is responsible for protein metabolism, the prevention of neural tube defects in pregnancy, blood cell production, and the synthesis of neurotransmitters. Individuals with folate deficiencies may suffer from anemia, depression and other mood disorders, and may give birth to babies with neural tube defects. Supplementation with folic acid may be useful in reversing these effects. 

A depressed uptake of deoxyuridine brought about by a deficiency of vitamin B12 can be reversed as reflected by a reduction in labeled thymidine uptake by the addition of as little as 1 xg of the vitamin. Folic acid added to a concentration of 50 p.g/ml of the culture will correct abnormal results due to folate deficiency and may partially correct abnormal results due to vitamin B12 deficiency. Abnormal results may occur in bone marrow from patients with iron deficiency and from patients being treated with 5-fluorouracil (B7). 

Both vitamin B12 and folate deficiencies are associated with psychiatric illness. Folate deficiency is most commonly associated with depression, whereas cognitive impairment and dementia are seen in about 25% of patients with either deficiency (Bottiglieri, 1996 Green and Miller, 1999). Herbert (1962) noted insomnia, forgetfulness, and irritability during the development of self-imposed folate deficiency which responded well to the administration of the vitamin. 

Adverse effects include CNS symptoms (reversible blurring of vision, diplopia, dizziness and ataxia) and depression of cardiac AV conduction. Alimentary symptoms, skin rashes, blood disorders and liver and kidney dysfunction also occur. Osteomalacia by enhanced metabolism of vitamin D (enzyme induction) occurs over years so also does folate deficiency. Enzyme induction reduces the efficacy of combined and progestogen-only contraceptives. Carbamazepine impairs cognitive function less than phenytoin. 

Importance of thiamine An important water-soluble vitamin used as a cofactor in enzymatic reactions involving the transfer of an aldehyde group. Without thiamine, individuals can develop dementia, macrocytic anemia (folate deficiency), gastritis, peptic ulcer disease, liver disease, depression, nutritional deficiencies, cardiomyopathy, and pancreatitis. 

Patients with folate deficiency and organic mental changes, polyneuropathy, and depression have been found to have a reduced cerebrospinal fluid level of 5-hydroxyindoleacetic acid. Following treatment with the vitamin the 5-hydroxyindoleacetic acid level was found to return to normal in those patients who showed improvement in their neuropsychiatric signs. However, patients who were folate deficient with neuropsychiatric symptoms which were not responsive to treatment with folic acid showed no change in their level of cerebrospinal 5-hydroxyindoleacetic acid (BIT). 

Many patients in intensive care units receive intravenous nutrition, which is a mixture of various amino acids, sorbitol, and ethanol. In a study of 30 patients with normal preoperative folate levels who were operated on for gastrointestinal disease, the serum folate fell within 48 hours by 60-95% in 20 patients receiving intravenous nutrition (W24). Seven patients had a megaloblastic bone marrow. Daily treatment with 0.5 mg of folic acid given intravenously prevented any clinical signs of folate deficiency. These patients received between 100 and 150 g of ethanol daily as part of their parenteral nutrition, and this may have played a significant role in the development of folate deficiency. However, Tennant (T12) examined this possibility and found that acute depression of the serum folate concentration occurred with both alcohol-firee and alcohol-containing preparations used for parenteral nutrition. It was also noted that only one particular brand of... 

As was mentioned earlier, reports by Shojania et al. (Sll, S12) of decreased plasma and red blood cell folate concentrations in users of OCAs first drew attention to this subject. Luhby et al. (LIO) also found evidence of folate deficiency in some women taking OCAs, and Wertalik et al. (W6) found lower plasma folate levels in women on the pill than in controls. It was felt (S12) that a large number of subjects given these agents for long periods of time needed to be studied in order to demonstrate a statistically significant difference, because folate concentrations were seldom profoundly depressed in such women. 

The manufacturers of pyrimethamine note that the concurrent use of zidovudine may increase the risk of bone marrow depression. They say that if signs of folate deficiency develop, then pyrimethamine should be discontinued and folinie acid given. Note that the prophylactic use of a folate supplement, preferably folinie acid, is recommended for all patients with toxoplasmosis taking high-dose pyrimethamine, to reduce the risk of bone marrow suppression. See also NRTIs Zidovudine + Myelosup-pressive drugs , p.809... 

Thornton and Thornton (1978) found 30% of psychiatric admissions to be folate-deficient Carney and Sheffield (1978) found 21% with levels below 2 ng/milliliter. Other investigators have found up to a 50% incidence of deficiency in psychiatric inpatients (Hallstrom, 1969). Carney and Sheffield (1970) retrospectively analyzed the effects of folate therapy on psychiatric inpatients with low serum folate. Of 102 such patients, a random 39 received supplementation. The treated patients with organic psychosis, depression, and schizophrenia improved more during their hospitalization than the untreated patients and had a significantly shortened hospital stay. 

Folate deficiency is associated with depression, psychogeriatric disease. 

In a report on an isolated case of peripheral lymphocyte response to mitogenic (PHA) stimulation from a patient with megaloblastic anemia due to folate deficiency. Das and Hoffbrand (1970) found a depressed incorporation of H-Thymidine, In a more extensive study, Gross et al. (1975) studied cell mediated immune function in twenty three Bantu patients in South Africa where there is a high incidence of megaloblastic anemia due to nutritional... 

Folate administration three days prior to immunization raised the level to 30/10. Decreased complement-fixation titers have also been observed by Wertman et al. (1952) in folate deficient rats. In an attempt to produce antibodies against the hapten p-aminobenzoylglutamate diazotized to bovine serum albumin, Rothenberg et al. (1973) found that antibody production was markedly depressed in folate-deficient mice and remained so many months following folate repletion even with repeated immunizing injections. Three months following supplementation there was a normal antibody response to SRBC injection but this parameter was never tested on the deficient animals. 

PHA (Stimulation index 14.8 in controls compared to 3.0 in folate deficient). An in vivo measurement of cell-mediated immune function (skin test sensitivity to intradermal PHA injection) showed a depressed response in the deficient animals based on the degree of mononuclear cell infiltration. 

Like folate and vitamin C, vitamin B6 (pyroxidine) is water soluble and like folate has several vitamers. Vitamin B6 may be involved in more bodily functions than any other nutrient (Tambasco-Studart et al., 2005), is a cofactor for many enzymes, especially those involved in protein metabolism, and is also a cofactor for folate metabolism. Vitamin B6 has anticancer activity (Theodoratou et al., 2008), is a strong antioxidant (Denslow et al., 2005), is involved in hemoglobin biosynthesis, lipid and glucose metabolism and immune and nervous system function. Possible consequences of deficiency include anemia, impaired immune function, depression, confusion, and dermatitis (Spinneker et al., 2007). Vitamin B6 deficiency is generally not a problem in the developed world, but there could be as yet poorly defined consequences of suboptimal intake particularly for the elderly. 

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