Compr Psychiatry 1997 Nov-Dec;38(6):305-14 Folate and cobalamin in psychiatric illness. Hutto BR Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, 27599, USA. The linkage of cobalamin and folate deficiency to psychiatric illness has been studied and debated since these vitamins were first discovered in the 1940s. The clinical relevance of these deficiencies remains the subject of investigation and scholarly discussion. This article reviews case reports and studies derived from a MEDLINE search for English-language articles related to folate, cobalamin, and psychiatric illness. Emphasis is given to clinical research and recent developments. Preclinical evidence for direct effects of folate and cobalamin on brain functioning is compelling, and numerous associations of their deficiencies to psychiatric illness are evident. These vitamin deficiencies may typically present initially with psychiatric symptoms, but any direct causal relationship to specific neuropsychiatric illnesses are not well defined. The relationship of these vitamins in dementia is significant, but they may only rarely be a cause of truly reversible dementia. Folate deficiency appears most tightly connected with depressive disorders, and cobalamin deficiency with psychosis. Contrary to intuition, vitamin deficiencies appear to occur infrequently with eating disorders. Other diagnoses have been investigated much less extensively. The diagnosis and management of these deficiencies in the context of neuropsychiatric illness is still a matter of discussion. The quality of clinical research in this area is improving, but there are many unanswered questions that affect clinical practice. Clinicians should remain vigilant to the possibility of deficiencies of folate and cobalamin in diverse psychiatric populations. Normal hematological indices do not rule out the deficiencies. Further study is needed to refine the detection and clinical management of these vitamin deficiencies in psychiatric populations. ---------- Nutr Rev 1997 May;55(5):145-9 Nutrition and depression: the role of folate. Alpert JE, Fava M Department of Psychiatry, Harvard Medical School, Boston, MA 02114, USA. A relationship between folate and neuropsychiatric disorders has been inferred from clinical observation and from the enhanced understanding of the role of folate in critical brain metabolic pathways. Depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency. Conversely, borderline low or deficient serum or red blood cell folate levels have been detected in 15-38% of adults diagnosed with depressive disorders. Recently, low folate levels have been linked to poorer antidepressant response to selective serotonin reuptake inhibitors. Factors contributing to low serum folate levels among depressed patients as well as the circumstances under which folate and its derivatives may have a role in antidepressant pharmacotherapy must be further clarified. ---------- Nutr Rev 1996 Dec;54(12):382-90 Folate, vitamin B12, and neuropsychiatric disorders. Bottiglieri T Kimberly H. Courtwright and Joseph W. Summers Institute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas, USA. Folate and vitamin B12 are required both in the methylation of homocysteine to methionine and in the synthesis of S-adenosylmethionine. S-adenosylmethionine is involved in numerous methylation reactions involving proteins, phospholipids, DNA, and neurotransmitter metabolism. Both folate and vitamin B12 deficiency may cause similar neurologic and psychiatric disturbances including depression, dementia, and a demyelinating myelopathy. A current theory proposes that a defect in methylation processes is central to the biochemical basis of the neuropsychiatry of these vitamin deficiencies. Folate deficiency may specifically affect central monoamine metabolism and aggravate depressive disorders. In addition, the neurotoxic effects of homocysteine may also play a role in the neurologic and psychiatric disturbances that are associated with folate and vitamin B12 deficiency. ---------- Med Hypotheses 1991 Feb;34(2):131-40 Subtle vitamin-B12 deficiency and psychiatry: a largely unnoticed but devastating relationship? Dommisse J A long list of psychiatrically inclined illnesses or symptoms, especially some cases of mood disorder, dementia, paranoid psychoses, violent behavior and fatigue, have been documented to be caused by vitamin-B12 deficiency, among other causes. The author uses reputably published literature--and extrapolations from it--to show that these conditions are possibly more commonly caused by B12 deficiency than is currently generally accepted, mostly because of a lack of appreciation of the lowest serum-B12 level that is necessary to protect against the cerebral manifestations of this deficiency. After surveying the whole area of psychiatry and nutritional deficiencies in general, the author deals with the role of vitamin-B12 in mood disorders, paranoid psychoses and dementia in more detail. In doing so, he cites some useful conclusions from the literature, including the debunking of several myths about the diagnosis and treatment of brain-B12-deficiency, especially the efficacy of high dose oral treatment and the relative inefficacy of the Schilling's test. ---------- Prog Neuropsychopharmacol Biol Psychiatry 1989;13(6):841-63 Folic acid and psychopathology. Young SN, Ghadirian AM Department of Psychiatry, McGill University, Montreal, Quebec, Canada. 1. The incidence of folic acid deficiency is high in patients with various psychiatric disorders including depression, dementia and schizophrenia. 2. In epileptics on anticonvulsants, folate deficiency often occurs because anticonvulsants inhibit folate absorption. In these patients folate deficiency is often associated with psychiatric symptoms. 3. In medical patients psychiatric symptoms occur more frequently, and in psychiatric patients symptoms are more severe, in those with folate deficiency than in those with normal levels. 4. Many open studies have demonstrated therapeutic effects of folate administration on psychiatric symptoms in folate deficient patients. 5. Several placebo-controlled studies have not demonstrated therapeutic effects, possibly because the doses they used (15-20 mg/day) are known to be toxic and to cause mental symptoms. 6. Two placebo-controlled studies have demonstrated beneficial effects of folic acid administration, one in patients with a syndrome of psychiatric and neuropsychological changes associated with folate deficiency and the other in patients on long-term lithium therapy. In the latter study the dose was only 0.2 mg/day. 7. Folic acid deficiency is known to lower brain S-adenosylmethionine and 5-hydroxytryptamine. S-Adenosylmethionine, which has antidepressant properties, raises brain 5-hydroxytryptamine. Thus, depression associated with folate deficiency is probably related to low brain 5HT. 8. S-Adenosylmethionine is involved in many methylation reactions, including methylation of membrane phospholipids, which influences membrane properties. This may explain the wide variety of symptoms associated with folate deficiency. 9. Because the costs and risks associated with low doses of folic acid (up to 0.5 mg/day) are small, folic acid should be given as an adjunct in the treatment of patients with unipolar or bipolar affective disorders and anorexia, epileptics on anticonvulsants, geriatric patients with mental symptoms and patients with gastrointestinal disorders who exhibit psychiatric symptoms. 10. Although the majority of the patients listed above will probably not be helped by folic acid therapy, a significant minority are likely to have folate-responsive symptoms. ---------- Nutr Rev 1989 Jul;47(7):208-10 Unrecognized cobalamin-responsive neuropsychiatric disorders. Neuropsychiatric disorders due to cobalamin deficiency occur in the absence of anemia or significant macrocytosis and may be overlooked because usual clinical laboratory tests are unreliable for diagnosis of cobalamin deficiency. Serum methylmalonic acid and homocysteine levels appear to be sensitive and accurate markers of cobalamin deficiency. ---------- Biol Psychiatry 1989 Apr 1;25(7):867-72 Folate, B12, and life course of depressive illness. Levitt AJ, Joffe RT Department of Psychiatry, University of Toronto, Ontario, Canada. Forty-four consecutive, unmedicated outpatients with a major depressive disorder were evaluated to determine the relationships in life course, severity of depressive illness, and serum folate and B12 levels. Duration of current episode was significantly inversely correlated with folate levels. Age at onset of illness was significantly correlated with B12. In a subgroup of recurrent depressives, current age and age at onset of depressive illness were positively correlated with folate. The findings are discussed in light of the current hypotheses regarding the association of folate and mood. ---------- J Psychiatr Res 1986;20(2):91-101 The biology of folate in depression: implications for nutritional hypotheses of the psychoses. Abou-Saleh MT, Coppen A Folate deficiency is a common occurrence in psychiatric disorders, whether organic or functional, particularly in depressive illness. We have shown that folate deficiency is a common association of depressive symptoms in a variety of settings including primary endogenous or non-endogenous depression, and in alcoholic, lithium-treated and anorexic patients. Possible pathogenetic mediating mechanisms for this association are methylation and hydroxylation and the implications for nutritional hypotheses of the psychoses are discussed. We suggest that folate deficiency, with or without deficiencies of other nutritional factors such as monoamine precursors, vitamins B6, B12 and C, may predispose to or aggravate psychiatric disturbances, particularly depression and a model for these interactions is proposed. ---------- Biol Psychiatry 1981 Feb;16(2):197-205 B12 deficiency and psychiatric disorders: case report and literature review. Zucker DK, Livingston RL, Nakra R, Clayton PJ Although an association of psychiatric symptoms with vitamin B12 deficiency is well accepted, the incidence and nature of these symptoms is not established. To help illuminate the natural history of this illness we review the literature regarding psychopathology associated with B12 deficiency and examine 15 cases, including one of our own, that meet specified criteria for B12-responsive psychosis. In the accepted cases the most common psychiatric symptoms were organic brain syndrome, paranoia, violence, and depression. Several of the patients were not anemic and had no neurologic deficit. Examination of blood smears or obtaining of serum B12 levels should be considered for patients with the symptoms described.