The Role of Minerals and Vitamins in Mental Health
Mental and Elemental Nutrients: A Physician's Guide to Nutrition and Health Care by Carl Pfeiffer, MD, PhD, 1976
Natural Healing for Schizophrenia & Other Common Mental Disorders by Eva Edelman, 1998
This excellent book embraces the approaches used by both Pfeiffer and Hoffer. A quote from William Walsh PhD, (co-founder and chief-scientist at the Pfeiffer Treatment Center), on the back cover states:
"This is the most useful volume on nutritional methods for mental illness written in the past 20 years. I believe that it will be a valuable resource for researchers, clinicians, and families alike. It is required reading for our research and medical staff."
All vitamins and minerals are involved in one or more biochemical pathways and/or physiological actions which influence the function of the human brain. Most vitamin and mineral deficiencies result in psychiatric symptoms in a significant number of people, and in people with psychiatric diagnoses these deficiencies are often associated with more severe symptoms and poorer outcome from conventional treatment. Vitamin and mineral deficiencies may act as an exacerbating factor secondary to malnutrition, alcoholism, etc. or may be a primary causative factor. Either way, optimisation of nutrient levels is in each patients best interest.
Vitamin B1 (thiamine).
Thiamine deficiency commonly results in psychiatric symptoms. Nine young men were deprived of thiamine to study the effects of thiamine deficiency. After thiamine deficiency was induced, 5/9 of the men developed marked irritability and depression. (J Broek. 1957) Another thiamine deprivation study reported symptoms of fearfulness, agitation and emotional instability. (RD Williams. 1943) In one study, low thiamine levels were significantly associated with reduced mood in women, but not in men, (Benton D. 1995) while another study reported thiamine deficient individuals were more anxious and more depressed based on ratings from the Adjective checklist, although not more depressed based on the Frieburg personality inventory scale. (Heseker H. 1992) Severe thiamine deficiency induced by chronic alcoholism, referred to as Wernicke-Korsakoff syndrome, is well known to be associated with a large array of psychiatric and cognitive symptoms. (Mann. 2000)
Thiamine is required for the activity of pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl-coenzyme A. If activity of this enzyme is impaired, excess pyruvate may be converted into lactate (H. Wick. 1977), which can cause anxiety. (RA Buist. 1985) Thiamine is also required for other aspects of energy metabolism. (Mann. 2000) High doses of thiamine (400 mg) have been documented to inhibit platelet monoamine oxidase activity (Connor DJ. 1981), although it is not clear if this is a pharmacological effect due to mega-doses or an effect achieved at normal physiological doses.
Investigations into thiamine status of psychiatric patients have produced mixed results. One study reported 0/36 inpatients with major depression, excluding those with high alcohol consumption, had thiamine deficiency upon laboratory testing, (Bell IR. 1991) while Carney reported 30% of 172 and 78% of 74 mixed psychiatric inpatients had low thiamine levels respectively. (MW Carney. 1982) (MW Carney. 1979) 7/12 agoraphobia patients were also found to be deficient in thiamine. (LC Abbey. 1981) Given that the one study excluding patients with alcoholism found no patients with thiamine deficiency (Bell IR. 1991), the discrepancy of these studies is probably due to thiamine deficiency being largely secondary to alcoholism and malnutrition present in many psychiatric patients. Differing laboratory techniques and reference ranges may also be another issue. Thiamine deficiency should be suspected in the presence of alcoholism and malnutrition.
Vitamin B2 (riboflavin).
A riboflavin deprivation study, undertaken with 6 male volunteers, examined the effect of riboflavin deficiency on aspects of personality and behaviour. (Ray T. Sterner. 1973) Results indicated increased levels of depression, hysteria, psychopathic-deviate behavior and hypomania in riboflavin deficient individuals. Chronically riboflavin deficient individuals were reported to be more depressed based on ratings from the Adjective checklist, although not more depressed based on the Frieburg personality inventory scale. (Heseker H. 1992)
Riboflavin is essential to many pathways involved in the metabolism of protein, fats and carbohydrates (Mann. 2000) and for the activity some P450 enzymes, involved in the metabolism of selected toxins and medications. (Rivlin RS. 1996) Riboflavin is also required for the activity of numerous antioxidant enzymes including glutathione reductase, which regenerates endogenous glutathione. In fact, the activity of glutathione reductase is used clinically and in research as a functional marker for riboflavin status. (Powers HJ. 1999) Relating to riboflavins antioxidant function, riboflavin deficiency has been associated with oxidative stress. (Rivlin RS. 1996) Major depression has also been associated with oxidative stress which may play a role in its development. (Bilici M. 2001)
A small amount of research has investigated riboflavin status in psychiatric patients. Of 36 inpatients with major depression, a significant number where deficient in riboflavin. (Bell IR. 1991) Of 172 consecutive mixed psychiatric inpatients, 27% were deficient in riboflavin (MW Carney. 1982) and 1/12 agoraphobia patients were deficient in riboflavin. (LC Abbey. 1982)
Vitamin B6 (pyridoxine).
A single human volunteer consumed a B6 free diet for 55 days. (Hawkins WW. 1948) Depression was a notable symptom which disappeared shortly after B6 supplementation commenced. Lower levels of pyridoxal phosphate, the biochemically active form of B6, are significantly correlated with higher levels of depression. (Hvas AM. 2004) Irritability and confusion have also been reported as symptoms of B6 deficiency (Leklem JE. 1991) and chronically B6 deficient individuals were also found to be significantly more anxious. (Heseker H. 1992)
Pyridoxine is required as a coenzyme for the synthesis of serotonin, dopamine and GABA. Pyridoxine is also required for carbohydrate metabolism and other aspects of amino acid metabolism. (Mann. 2000)
21/101 outpatients with major depression where found to have B6 deficiency while 14/21 B6 deficient patients displayed numbness, paresthesias and ‘electric shock’ sensations, typical of B6 deficiency. (Stewart JW. 1984) By measuring pyridoxal phosphate levels, 4/7 depressed patients and zero controls where found to be B6 deficient. (Russ CS. 1983) A more in depth evaluation of B6 status performed using an enzyme stimulation method revealed all 7 depressed patients and none of the controls were B6 deficient. Of 172 consecutive mixed psychiatric inpatients, 9% were deficient in B6. (MW Carney. 1982) Significantly more depressed patients, than other psychiatric diagnoses, where documented to have B6 deficiency (MW Carney. 1979) and 6/12 agoraphobia patients were deficient in B6. (LC Abbey. 1982) 19/39 women on oral contraceptives were deficient in B6 and when these 19 women where given B6 supplements 16/19 experienced improved mood. (Adams PW. 1973)
Depression is a common symptom of folate deficiency. (JE Alpert. 1997 & Howard JS. 1975) Of 1081 young men, those who were folate deficient were significantly more depressed based on ratings from the Adjective checklist, although not more depressed based on the Frieburg personality inventory scale. (Heseker H. 1992) Two more studies reported a significant association between folate level and depression ratings (Sachdev PS. 2005) (Bell IR. 1990), however, another investigating a group of 5948 subjects found no significant correlation between folate levels and depression or anxiety. (Bjelland I. 2003) The duration of current depressive episodes was also inversely correlated with serum folate levels in one study, which could be a reflection of dietary practices changing over the course of the illness. (Levitt AJ. 1989) Central nervous system abnormalities were found in two thirds of patients with megaloblastic anaemia due to folate deficiency with affective disorder being the most common association. (Shorvon SD. 1980)
Folates basic functions include methylation and DNA synthesis. (Mann. 2000) S-adenosylmethionine (SAMe) and tetrahydrobiopterin (BH4), both involved in monoamine synthesis, are lower in the presence of folate deficiency. (Young SN. 1989) (Bottiglieri T. 1992) Lower central nervous system levels of 5-hydroxytryptamine (serotonin) are also documented in folate deficiency. (Young SN. 1989) The most likely explanation for the association between folate status and psychiatric symptoms is its connection with monoamine metabolism via methylation, although other functions are also likely relevant. High plasma homocysteine levels have been shown to correlate strongly with low cerebrospinal fluid levels of folate, SAMe and monoamines. (T Bottiglieri. 2000) Homocystine levels are not raised in all cases of folate deficiency, so are not reliable marker for folate status. If elevated homocysteine levels are an innocent marker for folate, B12 and other deficiencies, or if elevated homocysteine also plays a direct role in major depression and anxiety disorders is unclear. (Bottiglieri T. 1996) Anemia and macrocytosis can be the result of folate deficiency, although they are only present in more severe cases so are also not a reliable predictor of folate status in psychiatric populations. (Mischoulon D. 2000)
A large body of research has examined the status of folate in psychiatric patients. 9/12 studies summarized below found folate deficiency in 17-31% of patients. The discrepancy between these 9/12 studies which reported high rates of deficiency and 3/12 studies reporting low rates, 0-3.4 %, is likely explained by different diets, alcohol consumption, laboratory techniques and reference ranges.
A prospective study followed 2,313 men aged between 42 and 60 for over 10 years. (T Tolmunen. 2004) At the beginning of the study, individual’s diets were analysed and divided into below and above the energy-adjusted median folate intake. Those below the median folate intake level had a relative risk of 3.04 (CI: 1.58-5.86) of receiving a diagnosis of depression.
Low serum folate levels were associated with a higher relapse rate in people with major depression being treated with fluoxetine. (Papakostas GI. 2004) In another study, high folate levels predicted greater improvement via SSRI’s in 22 depressed patients over 60 years old. (Murray. 2003) Low serum levels of 5-MeTHF, a biologically active form of folate, are not predictive of response to electroconvulsive therapy (ECT) in major depression. (Wilkinson AM. 1994)
Vitamin B12 (cobalamin).
Depression is a common early psychiatric manifestation of B12 deficiency. (Durand C. 2003 & Goodman KI. 1990 & Hector M. 1988) Other symptoms include mania and psychosis, (Hector M. 1988) and slowing of mental processes, confusion and memory defects. (Holmes JM. 1956) Of 1081 young men, those who were B12 deficient were significantly more anxious based on ratings from the Adjective checklist, although not more anxious based on the Frieburg personality inventory scale. (Heseker H. 1992)
B12 is a cofactor required for methionine synthase, which catalyses the conversion of homocysteine to methionine (Bottiglieri T. 1996), and is required for the production of energy from fatty acids and proteins. (Mann. 2000) Methionine is the direct precursor of S-adenosylmethionine (SAMe), which is involved in methylation reactions including neurotransmitter synthesis. B12 deficiency also causes folate to be ‘trapped’ in a form not available to perform its function. (Mann. 2000)
In one study, 47 patients with depression underwent high-resolution magnetic resonance imaging scans and B12 levels assessment. (Hickie I. 2005) Low B12 levels were found to be predictive of white matter lesions. Of 50 patients with B12 deficiency associated megaloblastic anaemia, 26% displayed organic mental changes and 16% had subacute combined degeneration of the spinal cord. (Shorvon SD. 1980) 8/9 patients with B12 deficiency and the absence of hematologic evidence of deficiency displayed abnormal evoked potential, evidence of electrophysiologic neurological impairment, while selected individuals had myelopathy, neuropathy and seizure disorders. (Karnaze DS. 1990) Low B12 status is associated with low RBC and WBC in psychiatric inpatients. (Carney MW. 1978) These haematological abnormalities are predictive of low B12, although their presence or absence does not confirm or rule out B12 deficiency. B12 deficiency has a major and well documented negative effect on neurological function.
A number of studies have investigated the presence of B12 deficiency in psychiatric populations. The discrepancy between different studies is likely explained by different diets (e.g. animal product consumption), laboratory techniques and reference ranges. The rate of deficiency varied between 3.7 and 26.1 %.
In psychiatric patients, low B12 levels correlate highly with depression rating scores (Levitt AJ. 2003) and, in healthy volunteers, those with chronically low B12 levels have significantly higher depression levels. (Heseker H. 1992) Other studies have not confirmed these associations. In a group of 5948 subjects aged 46 to 49 years, depression ratings, anxiety/depression ratings and B12 levels were assessed. No significant correlation was found between B12 levels and depression and anxiety. (Bjelland I. 2003) Another study of 412 persons aged 60-64 years also found no significant association between B12 levels and depression ratings. (Sachdev PS. 2005) Several studies have confirmed depressive patients who also had symptoms of psychosis tend to have lower B12 levels than depressive patients with no psychotic symptoms. (Bell IR. 1991 & Bell IR. 1990) Of 84 patients with megaloblastic anaemia, 50 had B12 deficiency. Of these 50 patients 20% had an affective disorder. (Shorvon SD. 1980)
In patients with major depression, higher B12 levels have been associated with improved treatment outcomes in one study (Hintikka J. 2003) while another using fluoxetine as the treatment agent found no association between B12 levels and treatment outcome. (Fava M. 1997)
Vitamin C (ascorbic acid).
Depression is a classic early symptom of vitamin C deficiency. (Robert E. 1971) In a vitamin C deprivation study, symptoms of depression, hypochondriasis, hysteria, reduced arousal and reduced motivational were documented. (Robert A. 1971) In a study of 1081 young men, those who were vitamin C deficient were significantly more anxious and people deficient in vitamin C were also significantly more depressed based on ratings from the Adjective checklist, although not more depressed based on the Frieburg personality inventory scale. (Heseker H. 1992)
Vitamin C is a cofactor for dopamine beta-hydroxylase (Kaufman S. 1966), which is involved in the conversion of dopamine to norepinephrine, and a cofactor for tryptophan-5-hydroxylase required for the conversion of tryptophan to 5-hydroxytryptophan (Cooper JR. 1961) in serotonin production. Vitamin C also has broad-spectrum antioxidant properties and is essential for the mitochondrial metabolism of fats. (Mann. 2000)
A group of patients depressed for 2-5 months had significantly reduced levels of vitamin C as compared to the non-depressed control group. (Singh RB. 1995) Another group of 885 patients in a psychiatric hospital had significantly lower vitamin C levels than controls, reporting 32% had readings below the range in which negative health effects have been clearly documented. (Schorah CJ. 1983) A group of chronic mixed psychiatric patients required a longer time period to achieve vitamin C saturation upon supplementation, suggesting lower vitamin C status. (G Milner. 1963) Another study reported over 10% of 465 psychiatric inpatients had markedly delayed vitamin C saturation indicating some degree of vitamin C insufficiency. (Leitner ZA. 1956)
Magnesium deficiency can cause depression, behaviour and personality changes, apathy, irritability and anxiety. (Wacker WE. 1968 & Freyre AV. 1970 & Rasmussen HH. 1989)
Magnesium is required by over 300 chemical reactions in humans. (Shils ME. 1999) Individuals with low cerebrospinal fluid levels of magnesium tend to have lower cerebrospinal fluid levels of 5-hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, indicating lower central nervous system serotonin levels. (Banki CM. 1985 & Banki CM. 1986) An animal study in which magnesium deficiency was induced in cows found magnesium deficiency was associated with reduced dopamine levels in the cerebral cortex and cerebellum and lower norepinephrine in the corpus striatum. (McCoy MA. 2000) The relevance of these findings to human magnesium deficiency is unclear. In humans, magnesium deficiency impairs the cardiovascular response to stress, while stress also increases magnesium requirements. (Seelig MS. 1994) Magnesium deficiency also leads to impaired glutamatergic transmission via NMDA-receptors (Siwek M. 2005) and an increase in the lactate to pyruvate ratio (RA Buist. 1985), both of which are relevant to psychiatric conditions.
Studies of plasma/serum magnesium levels in psychiatric patients have been mixed. In one study, plasma magnesium levels were significantly lower than controls and increased as patients showed clinical improvement. (Frizel D. 1969) Three other studies reported lower plasma levels than controls (Zieba A. 2000) (Kirov GK. 1990) (Frizel D. 1969), one study reported no differences (Manser WW. 1989) and three others found higher levels of plasma or serum magnesium in non-medicated depressed patients. (Widmer J. 1992) (Cade JF. 1964) (Hasey GM. 1993) Only 1% of magnesium in the human body is present in extracellular fluids (e.g. plasma/serum), making plasma/serum magnesium levels an unreliable marker for magnesium status. (Mann. 2000) A group of researchers examining plasma magnesium levels in psychiatric patients found no correlation between low plasma magnesium and increased anxiety levels. (Kirov GK. 1994) However 22.4% and 10.4% of patients had levels below and above the laboratory reference range respectively. There was a strong tendency for more disturbed and excitable patients to fall into either the abnormally low or high groups, suggesting a possible significance of impaired magnesium homeostasis.
Two studies found patients with major depression and affective disorders, respectively, showed no significant differences in RBC magnesium levels as compared to healthy controls. (Kamei K. 1998) (Ramsey TA. 1979) Another study reported 45 depressed patients had lower RBC magnesium levels than 31 controls (Rybakowski J. 1989), while another found higher levels of RBC magnesium in non-medicated depressed patients. (Widmer J. 1992) A study of more than 200 patients with depression and/or chronic pain documented 75% had below normal magnesium levels in white blood cells. (Shealy CN. 1990)
Cerebrospinal fluid (CSF) levels of magnesium were found to be lower in patients with major depression (n = 16) and adjustment disorder (n = 10), as compared with controls. (Banki CM. 1985) This research group also found that it was the psychiatric patients with a history of suicide attempts which had low CSF magnesium levels, pulling down the group average. Differences between depressed patients with no history of suicide attempts and healthy controls were insignificant. Another study by this same research group of 275 drug-free psychiatric patients confirmed both of these findings. (Banki CM. 1986) Levine and colleagues found an elevated Ca/Mg ratio in the CSF of depressed patients. (Levine J. 1999)
Psychiatric manifestations of zinc deficiency include behavioural disturbances, depression and mental confusion. (Mann. 2000) Within major depression populations, lower zinc levels correlate with higher depression severity. (Maes M. 1994)
Zinc plays a role in catalysing, and/or is an active constituent of, over 150 enzymes in humans. (Mann. 2000) Zinc is involved in such functions as antioxidant defence, gene expression, nerve impulse transmission, thyroid function, digestion and a large array of other functions. Zinc is found in high concentrations in hippocampal and cortical neurons. (Nowak G. 1998) Zinc is also an inducer of brain derived neurotrophic factor (Nowak G. 2005), is an antagonist of the NMDA-receptor (Nowak G. 2005 & 2001) and is required for GABA metabolism. (Nowak G. 1998) Zinc deficiency causes biological membranes to be more prone to oxidative damage and impaired function. (O'Dell BL. 2000) In one study of six young men, experimentally induced zinc deficiency was shown to reduce basal metabolic rate ~9% and also significantly reduced protein utilization. (Wada L. 1986)
Three consecutive studies by Maes and colleagues found serum zinc levels were significantly lower in depressed patients as compared to healthy matched controls. (Maes M. 1994, 1997 & 1999) Lower serum zinc was associated with higher past treatment resistance. (Maes M. 1997) In a group of 30 patients with mood disorders, 7/30 had a clear zinc deficiency. (Little KY. 1989) 14 patients with primary affective disorder were found on admission to hospital to have lower plasma zinc levels than 14 controls. (McLoughlin IJ. 1990) Another study reported slightly lower plasma zinc levels in depressed patients, although this did not reach statistical significance. (Narang RL. 1991)
Nowak and colleagues investigated zinc concentrations of 10 suicide victims compared to 10 age-matched controls. (Nowak G. 2003) Hippocampal or cortical tissue showed no differences in zinc content between groups although there was a 26% decrease in the inhibition by zinc of [(3)H]MK-801 binding to NMDA receptors in hippocampal tissue, but not in cortical tissue.
- Adams PW, et al. Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraceptives. Lancet 1973;1:897-904.
- Banki CM, Arato M, Kilts CD. Aminergic studies and cerebrospinal fluid cations in suicide. Ann N Y Acad Sci. 1986;487:221-30.
- Banki CM, Vojnik M, Papp Z, Balla KZ, Arato M. Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts. Biol Psychiatry. 1985 Feb;20(2):163-71.
- Bell IR, Edman JS, Marby DW, Satlin A, Dreier T, Liptzin B, Cole JO. Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population. Biol Psychiatry. 1990 Jan 15;27(2):125-37.
- Bell IR, Edman JS, Miller J, Hebben N, Linn RT, Ray D, Kayne HL. Relationship of normal serum vitamin B12 and folate levels to cognitive test performance in subtypes of geriatric major depression. J Geriatr Psychiatry Neurol. 1990 Apr-Jun;3(2):98-105.
- Bell IR, Edman JS, Morrow FD, Marby DW, Mirages S, Perrone G, Kayne HL, Cole JO. B complex vitamin patterns in geriatric and young adult inpatients with major depression. J Am Geriatr Soc. 1991 Mar;39(3):252-7.
- Benton D, Haller J, Fordy J. Vitamin supplementation for 1 year improves mood. Neuropsychobiology. 1995;32(2):98-105.
- Bilici M, Efe H, Koroglu MA, Uydu HA, Bekaroglu M, Deger O. Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J Affect Disord. 2001 Apr;64(1):43-51.
- Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland PM. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003 Jun;60(6):618-26.
- Bottiglieri T, Hyland K, Laundy M, Godfrey P, Carney MW, Toone BK, Reynolds EH. Folate deficiency, biopterin and monoamine metabolism in depression. Psychol Med. 1992 Nov;22(4):871-6.
- Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. 1996 Dec;54(12):382-90.
- Cade JF. A Significant Elevation of Plasma Magnesium Levels in Schizophrenia and Depressive States. Med J Aust. 1964 Feb 8;10:195-6.
- Carney MW, Chary TK, Laundy M, Bottiglieri T, Chanarin I, Reynolds EH, Toone B. Red cell folate concentrations in psychiatric patients. J Affect Disord. 1990 Jul;19(3):207-13.
- Carney MW, Sheffield BF. Associations of subnormal serum folate and vitamin B12 values and effects of replacement therapy. J Nerv Ment Dis. 1970 May;150(5):404-12.
- Carney MW, Sheffield BF. Serum folic acid and B12 in 272 psychiatric in-patients. Psychol Med. 1978 Feb;8(1):139-44.
- Carney MW. Serum folate values in 423 psychiatric patients. Br Med J. 1967 Dec 2;4(578):512-6
- Connor DJ. Thiamine intake and monoamine oxidase activity. Biol Psychiatry. 1981 Sep;16(9):869-72.
- Cooper JR. The role of ascorbic acid in the oxidation of tryptophan to 5-hydroxytryptophan. Ann NY Acad Sci 1961;92:208-11.
- Durand C, Mary S, Brazo P, Dollfus S. Psychiatric manifestations of vitamin B12 deficiency: a case report. Encephale. 2003 Nov-Dec;29(6):560-5.
- Edeh J, Toon BK. A general practice study of the prevalence of psychiatric morbidity and social handicap in epilepsy, in M Parsonage et al, Eds. Advances in Epileptology. XV Epilepsy International Symposium. New York, Raven Press, 1983.
- Edwin E, Holten K, Norum Kr, Schrumpf A, Skaug OE. Vitamin B12 Hypovitaminosis in Mental Diseases. Acta Med Scand. 1965 Jun;177:689-99.
- Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry. 1997 Mar;154(3):426-8.
- Freyre AV, Flichman JC. Spasmophilia caused by magnesium deficit. Psychosomatics. 1970 Sep-Oct;11(5):500-1.
- Frizel D, Coppen A, Marks V. Plasma magnesium and calcium in depression. Br J Psychiatry. 1969 Dec;115(529):1375-7.
- Frizel D, et al. Plasma magnesium and calcium in depression. Br J Psychiatry 1969;115:1375-7.
- G Milner. Ascorbic acid in chronic psychiatric patients: a controlled trial. Br J Psychiatry 1963;109:294-9.
- Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds EH. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990 Aug 18;336(8712):392-5.
- Goodman KI, Salt WB 2nd. Vitamin B12 deficiency. Important new concepts in recognition. Postgrad Med. 1990 Sep 1;88(3):147-50, 153-8.
- H. Wick, K. Schweizer, R. Baumgartner. Thiamine dependency in a patient with congenital lacticacidaemia due to pyruvate dehydrogenase deficiency. Inflammation Research. Volume 7, Number 3 / September, 1977.
- Hallstrom T. Serum B12 and folate concentrations in mental patients. Acta Psychiatr Scand. 1969;45(1):19-36.
- Hasey GM, D'Alessandro E, Cooke RG, Warsh JJ. The interface between thyroid activity, magnesium, and depression: a pilot study. Biol Psychiatry. 1993 Jan 15;33(2):133-5.
- Hawkins WW, Barsky J. An experiment on human vitamin B6 deprivation. Science 1948;108:284-6.
- Hector M, Burton JR. What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc. 1988 Dec;36(12):1105-12.
- Heseker H, Kubler W, Pudel V, Westenhoffer J. Psychological disorders as early symptoms of a mild-to-moderate vitamin deficiency. Ann N Y Acad Sci. 1992 Sep 30;669:352-7.
- Hickie I, Naismith S, Ward PB, Scott E, Mitchell P, Wilhelm K, Parker G. Vascular risk and low serum B12 predict white matter lesions in patients with major depression. J Affect Disord. 2005 Apr;85(3):327-32.
- Hintikka J, Tolmunen T, Tanskanen A, Viinamaki H. High vitamin B12 level and good treatment outcome may be associated in major depressive disorder. BMC Psychiatry. 2003 Dec 2;3:17.
- Holmes JM. Cerebral manifestations of vitamin-B12 deficiency. Br Med J. 1956 Dec 15;(5006):1394-8.
- Howard JS 3rd. Folate deficiency in psychiatric practice. Psychosomatics. 1975;16(3):112-5.
- Hvas AM, Juul S, Bech P, Nexo E. Vitamin B6 level is associated with symptoms of depression. Psychother Psychosom. 2004 Nov-Dec;73(6):340-3.
- J Broek, H Guetzkow. Psychologic Effects of Thiamine Restriction and Deprivation in Normal Young Men. American Journal of Clinical Nutrition, 1957.
- JE Alpert, M Fava. Nutrition and depression: the role of folate. Nutr Rev 55(5):145-9, 1997
- Kamei K, Tabata O, Muneoka K, Muraoka SI, Tomiyoshi R, Takigawa M. Electrolytes in erythrocytes of patients with depressive disorders. Psychiatry Clin Neurosci. 1998 Oct;52(5):529-33.
- Kaufman S. Coenzymes and hydroxylases: ascorbate and dopamine-beta-hydroxylase; tetrahydropteridines and phenylalanine and tyrosine hydroxylases. Pharmacol Rev. 1966 Mar;18(1):61-9.
- Kinsman RA, Hood J. Some behavioral effects of ascorbic acid deficiency. American Journal of Clinical Nutrition, Vol 24, 455-464, 1971.
- Kirov GK, Birch NJ, Steadman P, Ramsey RG. Plasma magnesium levels in a population of psychiatric patients: correlations with symptoms. Neuropsychobiology. 1994;30(2-3):73-8.
- Kirov GK, Tsachev KN. Magnesium, schizophrenia and manic-depressive disease. Neuropsychobiology. 1990;23(2):79-81.
- LC Abbey. Agoraphobia. J Orthomol Psychiatry, 11:243-59, 1982
- Lee S, Wing YK, Fong S. A controlled study of folate levels in Chinese inpatients with major depression in Hong Kong. J Affect Disord. 1998 Apr;49(1):73-7.
- Leitner ZA, Church IC. Nutritional studies in a mental hospital. Lancet. 1956 Apr 28;270(6922):565-7.
- Leklem JE. Vitamin B-6. In: Machlin L, ed. Handbook of Vitamins. New York: Marcel Decker Inc; 1991:341-378.
- Lerner 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 Feb;25(1):60-7.
- Levine J, Stein D, Rapoport A, Kurtzman L. High serum and cerebrospinal fluid Ca/Mg ratio in recently hospitalized acutely depressed patients. Neuropsychobiology. 1999;39(2):63-70.
- Levitt AJ, Joffe RT. Folate, B12 and thyroid function in depression. Biol Psychiatry. 1993 Jan 1;33(1):52-3.
- Levitt AJ, Joffe RT. Folate, B12, and life course of depressive illness. Biol Psychiatry. 1989 Apr 1;25(7):867-72.
- Little KY, Castellanos X, Humphries LL, Austin J. Altered zinc metabolism in mood disorder patients. Biol Psychiatry. 1989 Oct;26(6):646-8.
- M Fava, JS Borus, JE Alpert, AA Nierenberg, JF Rosenbaum and T Bottiglieri. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997; 154:426-428
- Maes M, De Vos N, Demedts P, Wauters A, Neels H. Lower serum zinc in major depression in relation to changes in serum acute phase proteins. J Affect Disord. 1999 Dec;56(2-3):189-94.
- Maes M, D'Haese PC, Scharpe S, D'Hondt P, Cosyns P, De Broe ME. Hypozincemia in depression. J Affect Disord. 1994 Jun;31(2):135-40.
- Maes M, Vandoolaeghe E, Neels H, Demedts P, Wauters A, Meltzer HY, Altamura C, Desnyder R. Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry. 1997 Sep 1;42(5):349-58.
- Mann J & Truswell AS. Essentials of Human Nutrition. 2nd edition. New York: Oxford University Press; 2002.
- Manser WW, Khan MA, Hasan KZ. Trace element studies on Karachi population. Part IV: Blood copper, zinc, magnesium and lead levels in psychiatric patients with depression, mental retardation and seizure disorders. J Pak Med Assoc. 1989 Oct;39(10):269-74.
- McCoy MA, Young PB, Hudson AJ, Davison G, Kennedy DG. Regional brain monoamine concentrations and their alterations in bovine hypomagnesaemic tetany experimentally induced by a magnesium-deficient diet. Res Vet Sci. 2000 Dec;69(3):301-7.
- McLoughlin IJ, Hodge JS. Zinc in depressive disorder. Acta Psychiatr Scand. 1990 Dec;82(6):451-3.
- Mischoulon D, Burger JK, Spillmann MK, Worthington JJ, Fava M, Alpert JE. Anemia and macrocytosis in the prediction of serum folate and vitamin B12 status, and treatment outcome in major depression. J Psychosom Res. 2000 Sep;49(3):183-7.
- Murray A, Raul RS, Enrique RP. Prediction of Treatment Response in Geriatric Depression From Baseline Folate Level: Interaction With an SSRI or a Tricyclic Antidepressant. Journal of Clinical Psychopharmacology. 23(3):309-313, June 2003.
- MW Carney, A Ravindran, MG Rinsler and DG Williams. Thiamine, riboflavin and pyridoxine deficiency in psychiatric in- patients. The British Journal of Psychiatry 141: 271-272 (1982)
- MW Carney, DG Williams and BF Sheffield. Thiamine and pyridoxine lack newly-admitted psychiatric patients. The British Journal of Psychiatry 135: 249-254 (1979)
- Narang RL, Gupta KR, Narang AP, Singh R. Levels of copper and zinc in depression. Indian J Physiol Pharmacol. 1991 Oct;35(4):272-4.
- Nowak G, Szewczyk B, Pilc A. Zinc and depression. An update. Pharmacol Rep. 2005 Nov-Dec;57(6):713-8.
- Nowak G, Szewczyk B, Sadlik K, Piekoszewski W, Trela F, Florek E, Pilc A. Reduced potency of zinc to interact with NMDA receptors in hippocampal tissue of suicide victims. Pol J Pharmacol. 2003 May-Jun;55(3):455-9.
- Nowak G, Zieba A, Dudek D, Schlegel-Zawadzka M, Pilc A. Zinc homeostasis and glutamatergic system in the pathogenesis and treatment of depression. Psychiatr Pol. 2001 Mar-Apr;35(2):257-66.
- Nowak G. Alterations in zinc homeostasis in depression and antidepressant therapy. Pol J Pharmacol. 1998 Jan-Feb;50(1):1-4.
- O'Dell BL. Role of zinc in plasma membrane function. J Nutr. 2000;130(5S Suppl):1432S-1436S.
- Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004 Aug;65(8):1090-5.
- Powers HJ. Current knowledge concerning optimum nutritional status of riboflavin, niacin and pyridoxine. Proc Nutr Soc. 1999;58(2):435-440.
- RA Buist. Anxiety neurosis: The lactate connection. Int Clin Nutr Rev, 5(1):1-4, 1985
- Ramsey TA, Frazer A, Mendels J. Plasma and erythrocyte cations in affective illness. Neuropsychobiology. 1979;5(1):1-10.
- Rasmussen HH, Mortensen PB, Jensen IW. Depression and magnesium deficiency. Int J Psychiatry Med. 1989;19(1):57-63.
- Ray T. Sterner and Wayne R. Price. Restricted riboflavin: within-subject behavioral effects in humans. American Journal of Clinical Nutrition, Vol 26, 150-160, 1973
- RD Williams, HL Mason, MH Power, RM Wilder. Induced thiamine (vitamin B1) deficiency in man; relation of depletion of thiamine to development of biochemical defect and of polyneuropathy. Arch Int Med. 71:38-53, 1943.
- Reynolds EH, Preece JM, Bailey J, Coppen A. Folate deficiency in depressive illness. Br J Psychiatry. 1970 Sep;117(538):287-92.
- Rivlin RS. Riboflavin. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:167-173.
- Robert E. Hodges, James Hood, John E. Canham, Howerde E. Sauberlich, and Eugene M. Baker. Clinical manifestations of ascorbic acid deficiency in man. American Journal of Clinical Nutrition, Vol 24, 432-443, 1971.
- Russ CS. Vitamin B6 status of depressed and obsessive-compulsive patients. Nutr Rep Int 1983;27:867-873.
- Rybakowski J, Jankowiak E. Plasma and erythrocyte electrolytes in endogenous depression --neurophysiologic implications. Psychiatr Pol. 1989 Jul-Aug;23(4):265-70.
- Sachdev PS, Parslow RA, Lux O, Salonikas C, Wen W, Naidoo D, Christensen H, Jorm AF. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med. 2005 Apr;35(4):529-38
- Schorah CJ, Morgan DB, Hullin RP. Plasma vitamin C concentrations in patients in a psychiatric hospital. Hum Nutr Clin Nutr. 1983 Dec;37(6):447-52.
- Seelig MS. Consequences of magnesium deficiency on the enhancement of stress reactions; preventive and therapeutic implications (a review). J Am Coll Nutr. 1994 Oct;13(5):429-46.
- Shealy CN, et al. Magnesium deficiency in depression and chronic pain. Magnesium Trace Elem 1990;9:333.
- Shils ME. Magnesium. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:169-192.
- Shorvon SD, Carney MW, Chanarin I, Reynolds EH. The neuropsychiatry of megaloblastic anaemia. Br Med J. 1980 Oct 18;281(6247):1036-8.
- Singh RB, Ghosh S, Niaz MA, Singh R, Beegum R, Chibo H, Shoumin Z, Postiglione A. Dietary intake, plasma levels of antioxidant vitamins, and oxidative stress in relation to coronary artery disease in elderly subjects. Am J Cardiol. 1995 Dec 15;76(17):1233-8.
- Siwek M, Wrobel A, Dudek D, Nowak G, Zieba A. The role of copper and magnesium in the pathogenesis and treatment of affective disorders. Psychiatr Pol. 2005 Sep-Oct;39(5):911-20.
- Stewart JW, Harrison W, Quitkin F, Baker H. Low B6 levels in depressed outpatients. Biol Psychiatry. 1984 Apr;19(4):613-6.
- T Bottiglieria, M Laundya, R Crellinb, BK Tooneb, MWP Carneyc, EH Reynoldsa. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000;69:228-232
- Tolmunen T, Hintikka J, Ruusunen A, Voutilainen S, Tanskanen A, Valkonen VP, Viinamaki H, Kaplan GA, Salonen JT. Dietary folate and the risk of depression in Finnish middle-aged men. A prospective follow-up study. Psychother Psychosom. 2004 Nov-Dec;73(6):334-9.
- Wacker WE, Parisi AF. Magnesium metabolism. N Engl J Med. 1968 Apr 4;278(14):772-6 concl.
- Wada L, King JC. Effect of low zinc intakes on basal metabolic rate, thyroid hormones and protein utilization in adult men. J Nutr. 1986 Jun;116(6):1045-53.
- Widmer J, Bovier P, Karege F, Raffin Y, Hilleret H, Gaillard JM, Tissot R. Evolution of blood magnesium, sodium and potassium in depressed patients followed for three months. Neuropsychobiology. 1992;26(4):173-9.
- Wilkinson AM, Anderson DN, Abou-Saleh MT, Wesson M, Blair JA, Farrar G, Leeming RJ. 5-Methyltetrahydrofolate level in the serum of depressed subjects and its relationship to the outcome of ECT. J Affect Disord. 1994 Nov;32(3):163-8.
- Wolfersdorf M, Maier V, Froscher W, Laage M, Straub R. Folic acid deficiency in patients hospitalized with depression? A pilot study of clinical relevance. Nervenarzt. 1993 Apr;64(4):269-72.
- Young SN, Ghadirian AM. Folic acid and psychopathology. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13(6):841-63.
- Zieba A, Kata R, Dudek D, Schlegel-Zawadzka M, Nowak G. Serum trace elements in animal models and human depression: Part III. Magnesium. Relationship with copper. Hum Psychopharmacol. 2000 Dec;15(8):631-635.