Folate & Vitamin B-12 and Depression

A MEDLINE Search By, Ivan Goldberg, MD

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.