Taylor MJ, Carney S, Geddes J, Goodwin G.
for depressive disorders.
Cochrane Database Syst Rev. 2003;(2):CD003390.
There are a number of effective interventions for the treatment of depression.
It is possible that the efficacy of these treatments will be improved further
by the use of adjunctive therapies such as folate. OBJECTIVES: 1. To determine
the effectiveness of folate in the treatment of depression 2. To determine the
adverse effects and acceptability of treatment with folate. SEARCH STRATEGY: The
Cochrane Controlled Trials Register (CCTR), and the Cochrane Collaboration Depression,
Anxiety and Neurosis Controlled Trials Register (CCDANCTR) incorporating results
of group searches of EMBASE, MEDLINE, LILACS, CINAHL, PSYNDEX and PsycLIT were
searched. Reference lists of relevant papers and major textbooks of affective
disorder were checked. Experts in the field and pharmaceutical companies were
contacted regarding unpublished material. SELECTION CRITERIA: All randomised controlled
trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid
to an alternative treatment, whether another antidepressant medication or placebo,
for patients with a diagnosis of depressive disorder (diagnosed according to explicit
criteria). DATA COLLECTION AND ANALYSIS: Data were independently extracted from
the original reports by two reviewers. Statistical analysis was conducted using
Review Manager version 4.1. MAIN RESULTS: Three trials involving 247 people were
included. Two studies involving 151 people assessed the use of folate in addition
to other treatment, and found that adding folate reduced Hamilton Depression Rating
Scale scores on average by a further 2.65 points (95% confidence interval 0.38
to 4.93). Fewer patients treated with folate experienced a reduction in their
HDRS score of less than 50% at ten weeks (relative risk (RR) 0.47, 95% CI 0.24
to 0.92) The number needed to treat with folate for one additional person to experience
a 50% reduction on this scale was 5 (95% confidence interval 4 to 33). One study
involving 96 people assessed the use of folate instead of the antidepressant trazodone
and did not find a significant benefit from the use of folate. The trials identified
did not find evidence of any problems with the acceptability or safety of folate.
REVIEWER'S CONCLUSIONS: The limited available evidence suggests folate may have
a potential role as a supplement to other treatment for depression. It is currently
unclear if this is the case both for people with normal folate levels, and for
those with folate deficiency." [Abstract]
M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T.
vitamin B12, and homocysteine in major depressive disorder.
J Psychiatry. 1997 Mar;154(3):426-8.
"OBJECTIVE: The authors examined
the relationships between levels of three metabolites (folate, vitamin B12, and
homocysteine) and both depressive subtype and response to fluoxetine treatment
in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to
213 outpatients with major depressive disorder. At baseline, depressive subtypes
were assessed, and a blood sample was collected from each patient. Serum metabolite
levels were assayed. Response to treatment was determined by percentage change
in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with
low folate levels were more likely to have melancholic depression and were significantly
less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated
with depressive subtype or treatment response. CONCLUSIONS: Overall, the results
are consistent with findings linking low folate levels to poorer response to antidepressant
treatment. Folate levels might be considered in the evaluation of depressed patients
who do not respond to antidepressant treatment." [Abstract]
J, Tolmunen T, Tanskanen A, Viinamaki H.
High vitamin B12 level and
good treatment outcome may be associated in major depressive disorder.
Psychiatry. 2003 Dec 2;3(1):17.
"BACKGROUND: Despite of an increasing
body of research the associations between vitamin B12 and folate levels and the
treatment outcome in depressive disorders are still unsolved. We therefore conducted
this naturalistic prospective follow-up study. Our aim was to determine whether
there were any associations between the vitamin B12 and folate level and the six-month
treatment outcome in patients with major depressive disorder. Because vitamin
B12 and folate deficiency may result in changes in haematological indices, including
mean corpuscular volume, red blood cell count and hematocrit, we also examined
whether these indices were associated with the treatment outcome. METHODS: Haematological
indices, erythrocyte folate and serum vitamin B12 levels were determined in 115
outpatients with DSM-III-R major depressive disorder at baseline and serum vitamin
B12 level again on six-month follow-up. The 17-item Hamilton Depression Rating
Scale was also compiled, respectively. In the statistical analysis we used chi-squared
test, Pearson's correlation coefficient, the Student's t-test, analysis of variance
(ANOVA), and univariate and multivariate linear regression analysis. RESULTS:
Higher vitamin B12 levels significantly associated with a better outcome. The
association between the folate level and treatment outcome was weak and probably
not independent. No relationship was found between haematological indices and
the six-month outcome. CONCLUSION: The vitamin B12 level and the probability of
recovery from major depression may be positively associated. Nevertheless, further
studies are suggested to confirm this finding." [Full
Botez MI, Young SN, Bachevalier J, Gauthier
Effect of folic acid and vitamin B12 deficiencies on 5-hydroxyindoleacetic
acid in human cerebrospinal fluid.
Ann Neurol. 1982 Nov;12(5):479-84.
were measured in cerebrospinal fluid (CSF) from control patients, from patients
suffering from folate deficiency, and from patients with vitamin B12 deficiency.
The folate-deficient patients were classified according to whether they exhibited
a neuropsychiatric syndrome, consisting of organic mental changes, polyneuropathy,
and depression, which responded to folate administration. CSF 5-hydroxyindoleacetic
acid was low in the vitamin B12-deficient patients and in those folate-deficient
patients whose symptoms were not related to folate deficiency. CSF 5-hydroxyindoleacetic
acid returned to normal with folate treatment in the patients exhibiting folate-responsive
neuropsychiatric signs. The data indicate a close association between folate-responsive
neuropsychiatric symptoms and changes in 5-hydroxytryptamine metabolism in the
central nervous system." [Abstract]
T, Hyland K, Laundy M, Godfrey P, Carney MW, Toone BK, Reynolds EH.
deficiency, biopterin and monoamine metabolism in depression.
Med. 1992 Nov;22(4):871-6.
"Seven (21%) of 34 patients with a severe DSM-III
diagnosis of major depression had red-cell folate levels below 150 ng/ml. This
subgroup with folate deficiency had significantly lower CSF 5-hydroxyindoleacetic
acid (5HIAA) compared to neurological controls. For all depressed patients red-cell
folate was significantly correlated with CSF 5HIAA and homovanillic acid (HVA).
CSF tetrahydrobiopterin (BH4) was significantly correlated with CSF 5HIAA and
HVA and red-cell folate. Our observations provide further evidence of the links
between folate, biopterin and monoamine metabolism in depression." [Abstract]
R, Heales S, Bowron A.
Association of cerebrospinal fluid deficiency
of 5-methyltetrahydrofolate, but not S-adenosylmethionine, with reduced concentrations
of the acid metabolites of 5-hydroxytryptamine and dopamine.
Sci (Lond). 1994 Jun;86(6):697-702.
"1. Folate deficiency, or inborn errors
of folate metabolism, cause reduced turnover of 5-hydroxytryptamine (serotonin),
and perhaps dopamine, in the central nervous system. The mechanism by which this
occurs are not known. One possibility is that this is mediated by deficiency of
the methyl-donor S-adenosylmethionine. 2. To test this in humans, we have measured
cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid and homovanillic
acid, metabolites of 5-hydroxytryptamine and dopamine, respectively, in children
with inborn errors of the methyl-transfer pathway. These children are naturally
deficient in 5-methyltetrahydrofolate, S-adenosylmethionine or both before treatment,
and replete with S-adenosylmethionine, but not necessarily with 5-methyltetrahydrofolate,
during treatment. 3. Children with subnormal cerebrospinal fluid concentrations
of 5-methyltetrahydrofolate had significantly reduced concentrations of 5-hydroxyindoleacetic
acid and homovanillic acid. Children with subnormal cerebrospinal fluid concentrations
of S-adenosylmethionine did not have significantly reduced concentrations of these
metabolites. 4. We conclude that the mechanism by which deficiency of 5-methyltetrahydrofolate
causes reduced 5-hydroxytryptamine and dopamine turnover is unlikely to be mediated
by S-adenosylmethionine." [Abstract]
Wolfersdorf M, Keller F, Maier V, Froscher W, Kaschka
Red-cell and serum folate levels in depressed inpatients who
commit violent suicide: a comparison with control groups.
"There has been some discussion in the recent literature
regarding the possible relationship between peripheral levels of folate and serotonin
deficiency in the CNS. At the same time, such a serotonin deficiency has been
implicated in the biology of suicidal behavior. Thus, decreased peripheral folate
levels may be expected in patients who commit violent suicide. In this study,
the red-cell and serum folate levels in nine persons who later committed suicide
are compared with those in age- and sex-matched control groups. A one-way analysis
of variance showed no significant difference between the groups." [Abstract]
The use of diet and dietary components in the study of factors
controlling affect in humans: a review.
J Psychiatry Neurosci
"Although one of the first biological treatments
of a major psychiatric disorder was the dietary treatment of pellagra, the use
of diet and dietary components in the study of psychopathology has not aroused
much interest. This article reviews three areas in which the dietary approach
has provided interesting information. The tryptophan depletion strategy uses a
mixture of amino acids devoid of tryptophan to lower brain tryptophan in order
to study the symptoms that can be elicited. One effect of tryptophan depletion
is a lowering of mood, the magnitude of which seems to depend on the baseline
state of the subject. Therefore, recovered depressed patients often undergo an
acute relapse, while normal subjects show more moderate changes of mood. Totally
euthymic subjects show no lowering of mood, but subjects with high normal depression
scale scores or subjects with a family history of depression show a moderate lowering
of mood. These data indicate that low serotonin levels alone cannot cause depression.
However, serotonin does have a direct effect on mood, and low levels of serotonin
contribute to the etiology of depression in some depressed patients. Folic acid
deficiency causes a lowering of brain serotonin in rats, and of cerebrospinal
fluid 5-hydroxyindoleacetic acid in humans. There is a high incidence of folate
deficiency in depression, and there are indications in the literature that some
depressed patients who are folate deficient respond to folate administration.
Folate deficiency is known to lower levels of S-adenosylmethionine, and S-adenosylmethionine
is an antidepressant that raises brain serotonin levels. These data suggest that
low levels of serotonin in some depressed patients may be a secondary consequence
of low levels of S-adenosylmethionine. They also suggest that the dietary intake
and psychopharmacological action of methionine, the precursor of S-adenosylmethionine,
should be studied in patients with depression. Normal meals have definite effects
on mood and performance in humans. The composition of the meal, in terms of protein
and carbohydrate content, can influence these behaviors. Because protein and carbohydrate
meals can influence brain serotonin in rats, these effects in humans have usually
been interpreted in terms of altered serotonin functioning. However, the current
balance of evidence is against the involvement of serotonin in the acute effects
of protein and carbohydrate meals in humans. The underlying mechanisms involved
are unknown, but there are a variety of possibilities." [Abstract]
A, Bailey J.
Enhancement of the antidepressant action of fluoxetine
by folic acid: a randomised, placebo controlled trial.
Affect Disord. 2000 Nov;60(2):121-30.
"BACKGROUND: A consistent finding
in major depression has been a low plasma and red cell folate which has also been
linked to poor response to antidepressants. The present investigation was designed
to investigate whether the co-administration of folic acid would enhance the antidepressant
action of fluoxetine. METHODS: 127 patients were randomly assigned to receive
either 500 microg folic acid or an identical looking placebo in addition to 20
mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression
and had a baseline Hamilton Rating Scale (17 item version) score for depression
of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine
were carried out. RESULTS: Patients receiving folate showed a significant increase
in plasma folate.This was less in men than in women. Plasma homocysteine was significantly
decreased in women by 20.6%, but there was no significant change in men. Overall
there was a significantly greater improvement in the fluoxetine plus folic acid
group. This was confined to women where the mean Hamilton Rating Scale score on
completion was 6.8 (S.D. 4. 1) in the fluoxetine plus folate group, as compared
to 11.7 (S.D. 6. 7) in the fluoxetine plus placebo group (P<0.001).A percentage
of 93. 9 of women, who received the folic acid supplement, showed a good response
(>50% reduction in score) as compared to 61.1% of women who received placebo
supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid
group reported symptoms possibly or probably related to medication, whereas in
the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05).
LIMITATIONS AND CONCLUSIONS: Folic acid is a simple method of greatly improving
the antidepressant action of fluoxetine and probably other antidepressants. Folic
acid should be given in doses sufficient to decrease plasma homocysteine. Men
require a higher dose of folic acid to achieve this than women, but more work
is required to ascertain the optimum dose of folic acid." [Abstract]
Alpert JE, Mischoulon D, Rubenstein GE, Bottonari
K, Nierenberg AA, Fava M.
Folinic acid (Leucovorin) as an adjunctive
treatment for SSRI-refractory depression.
Ann Clin Psychiatry.
"Low folate is associated with poorer response to
selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD).
Folate supplementation in MDD has been studied in other settings with promising
results. The objective of this study was to assess the efficacy of methylfolate
as an adjunctive treatment among adults with MDD and inadequate response to an
SSRI. Twenty-two adults (59% female; mean age 45.2 +/- 11.0 years) with DSM-IV
MDD, partial or nonresponse to an SSRI after at least 4 weeks of treatment, and
a 17-item Hamilton Depression Rating Scale (HAM-D-17) score > or = 12 were
enrolled in this 8-week prospective open trial. Exclusion criteria included current
use of anticonvulsants or psychotropics other than an SSRI, or B12 deficiency.
Leucovorin (folinic acid), which is metabolized to methylfolate, was added to
SSRIs at 15-30 mg/day. Folate levels rose from 28 +/- 19 ng/mL to 301 +/- 203
ng/mL (p < 0.001). HAM-D-17 scores among the 16 completers decreased from 19.1
+/- 3.9 to 12.8 +/- 7.0 (p < 0.01). However only 31% of completers and 27%
of the intent-to-treat (ITT) sample achieved response (> or = 50% reduction
in HAM-D-17 scores), and only 19% of completers and 18% of the ITT sample achieved
remission (HAM-D-17 < or = 7). Leucovorin appears to be modestly effective
as an adjunct among SSRI-refractory depressed individuals with normal folate levels.
The application of leucovorin as an adjunct in the setting of refractory depression
deserves further study." [Abstract]
Enhancement of recovery from psychiatric
illness by methylfolate.
Br J Psychiatry. 1991 Aug;159:271-2.
(33%) of 123 patients with acute psychiatric disorders (DSM III diagnosis of major
depression or schizophrenia) had borderline or definite folate deficiency (red-cell
folate below 200 micrograms/l) and took part in a double-blind, placebo-controlled
trial of methylfolate, 15 mg daily, for 6 months in addition to standard psychotropic
treatment. Among both depressed and schizophrenic patients methylfolate significantly
improved clinical and social recovery. The differences in outcome scores between
methylfolate and placebo groups became greater with time. These findings add to
the evidence implicating disturbances of methylation in the nervous system in
the biology of some forms of mental illness." [Abstract]
PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, Chanarin I, Reynolds
Enhancement of recovery from psychiatric illness by methylfolate.
1990 Aug 18;336(8712):392-5.
"41 (33%) of 123 patients with acute psychiatric
disorders (DSM III diagnosis of major depression or schizophrenia) had borderline
or definite folate deficiency (red-cell folate below 200 micrograms/l) and took
part in a double-blind, placebo-controlled trial of methylfolate, 15 mg daily,
for 6 months in addition to standard psychotropic treatment. Among both depressed
and schizophrenic patients methylfolate significantly improved clinical and social
recovery. The differences in outcome scores between methylfolate and placebo groups
became greater with time. These findings add to the evidence implicating disturbances
of methylation in the nervous system in the biology of some forms of mental illness."
VA, Levitt AJ, Joffe RT.
Change in folate status with antidepressant
Psychiatry Res. 1994 Sep;53(3):313-22.
consecutive unmedicated outpatients with a major depressive illness had blood
drawn for measurement of serum folate (SF), red cell folate (RCF), and vitamin
B12 within 24 hours of completion of ratings of severity of depression at the
beginning and ending of a 5-week trial of desmethylimipramine (mean dose = 149.2
mg/day, range = 75-225 mg). As compared with nonresponders, responders had a significantly
higher mean SF at baseline (nonresponders = 13.8 nmol/l; responders = 17.7 nmol/l)
and RCF showed a significant inverse correlation with severity of depression and
a significant positive correlation with age of onset of illness. At week 5, change
in severity of depression was significantly correlated with change in RCF, and
significantly more responders than nonresponders had an increase in RCF. The possible
role of folate status in the regulation of mood and response to treatment is discussed."
GP, Fava M, Mazzi F, la Greca P.
An open trial of methyltetrahydrofolate
in elderly depressed patients.
Ann Clin Psychiatry. 1993
"5-methyltetrahydrofolate (MTHF) is a naturally occurring
substance involved in the synthesis of s-adenosyl-l-methionine (SAMe), a major
source of methyl groups in the brain. To assess the efficacy of a gastro-resistant,
oral preparation of MTHF, 20 elderly patients with a DSM-III-R diagnosis of depressive
disorder and a HAM-D-21 score > or = 18 underwent 6-weeks of open-label treatment
with 50 mg per day of oral MTHF. Of these 20 patients, 16 completed at least 4
weeks of treatment and showed a markedly significant improvement in their depressive
symptoms at endpoint, with 81% of them being considered responders. There were
no clinically relevant changes in the routine laboratory tests during the study,
and no adverse events considered to be definitely drug-related were reported."
S, Wing YK, Fong S.
A controlled study of folate levels in Chinese
inpatients with major depression in Hong Kong.
Disord. 1998 Apr;49(1):73-7.
"BACKGROUND: Although Western and, in particular,
British studies have revealed a substantial rate of hypofolatemia in patients
with depression, few such studies have been conducted in Asian populations. METHODS:
A group of 117 newly admitted inpatients with DSM-III-R major depression and 72
healthy controls underwent blood investigations and psychometric assessments.
RESULTS: Patients had a significantly lower mean serum folate level (24.6+/-10.2
vs. 30.3+/-11.4 nmol/l, P < 0.001) but a higher mean erythrocyte folate level
(801.8+/-284.6 nmol/l vs. 699.5+/-248.7 nmol/l, P < 0.01) than control subjects.
No patient or control subjects had low folate, while only four patients (3.4%)
and six control subjects (8.3%) had low erythrocyte folate. Folate levels were
not related to patients' age, duration of illness, Hamilton Depression Rating
Scale, Beck Depression Inventory and Global Assessment Scale scores, and prior
psychotropic drug usage. Both patients and control subjects revealed a high intake
of green vegetables. CONCLUSION: Patients' lower serum folate level was likely
to be secondary to their depression but, being well in the normal range, should
not have aggravated their depressive symptoms. Culturally patterned health beliefs
and dietary practices can influence the connection between folate status and depression
in different societies. LIMITATIONS: Patients were not drug-free, while the lack
of detailed dietary analysis and longitudinal data on folate level and psychiatric
outcome tempered the above conclusion. CLINICAL RELEVANCE: Since normofolatemia
is normative in Hong Kong, the routine screening of folate levels in Chinese depressive
patients is not indicated. However, a double-blind, placebo-controlled trial may
be useful for finding out whether Chinese patients will still benefit from folate
AM, Anderson DN, Abou-Saleh MT, Wesson M, Blair JA, Farrar G, Leeming RJ.
level in the serum of depressed subjects and its relationship to the outcome of
J Affect Disord. 1994 Nov;32(3):163-8.
5-MeTHF levels are reported in 26 subjects, before and after completing a course
of ECT, and compared to 21 healthy volunteers. 5-MeTHF levels of depressed subjects
were significantly lower than controls before and after ECT. There was no difference
in 5-MeTHF levels between ECT responders and non-responders but folate deficiency
was related to severity of depression before ECT. Serum 5-MeTHF was not related
to treatment response and values remained markedly low even after a good response
to treatment." [Abstract]
D, Burger JK, Spillmann MK, Worthington JJ, Fava M, Alpert JE.
and macrocytosis in the prediction of serum folate and vitamin B12 status, and
treatment outcome in major depression.
J Psychosom Res.
"BACKGROUND: Folate and B12 deficiencies may result
in macrocytic anemia, and are common in major depression; hypofolatemia may result
in poorer antidepressant response. We wished to determine whether anemia or macrocytosis
predict hypofolatemia, low B12, or refractoriness to antidepressants. METHODS:
After obtaining serum folate, B12, and hematological indices, 213 depressed adults
were treated with fluoxetine 20 mg/day. Amelioration of depressive symptoms was
measured. RESULTS: Neither macrocytosis nor anemia predicted low serum folate/B12,
or antidepressant refractoriness. Among 39 patients with hypofolatemia, none had
macrocytosis; 28% had low HCT; 41% had low RBC. Among 25 patients with low B12,
none had macrocytosis; 24% had low HCT; 28% had low RBC. Among non-responders,
3% had macrocytosis; 24% had low HCT; 25% had low RBC. CONCLUSION: Anemia and
macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness
to antidepressants. Measurement of folate and B12 should be considered when evaluating
treatment refractoriness." [Abstract]
M, Ozcan O, Avsar K, Cetin M, Ozdemir AS, Gok M.
acid measurements for the assessment of cobalamin deficiency related to neuropsychiatric
Clin Biochem. 2003 Jun;36(4):275-82.
Detection of cobalamin deficiency is clinically important for a better understanding
of neuropsychiatric diseases, and why the deficiency occurs more frequently than
previously anticipated. However, serum cobalamin measurements have a limited ability
to diagnose a deficiency state. OBJECTIVE: To evaluate functional cobalamin status
in neuropsychiatric patients using an appropriate photometric urine methylmalonic
acid (MMA) determination method that could be easily adapted to all routine clinical
laboratories. METHODS: We modified the old photometric method used for determining
urinary MMA concentrations. MMA measurements were made in first morning urine
samples with normalizing by creatinine concentrations. The serum cobalamin, total
homocysteine (tHcy), folate, red cell folate, and urinary MMA concentrations taken
from 17 psychosis, 28 depression, 16 dementia patients and 47 healthy people were
analyzed using the ROC, correlation and multiple regression analysis.RESULTS:
The modified method was found to have better recovery (96-103%) and CV% values
than the old method. Mean +/- SDs of uMMA and cobalamin concentrations were 11.49
+/- 4.93 mmol/mol creatinine, and 231 +/- 151 pg/mL in psychosis and depression
group, and 6.04 +/- 1.93 mmol/mol creatinine and 308 +/- 140 pg/mL in control
group, respectively. Those in the dementia group were 11.53 +/- 4.0 mmol/mol creatinine
and 231 +/- 84 pg/mL, and in the control group 6.05 +/- 1.94 mmol/mol creatinine
and 364 +/- 188 pg/mL. There was a good correlation between urinary MMA and serum
Vitamin B(12) determinations for all groups at a confidence level (p) of 99%.
The correlation between urinary MMA and red cell folate was also significant at
p = 95% for depression, psychosis and control groups, and p = 99% for dementia
group. In the ROC analyses, area under the curve values for uMMA, B12 and tHcy
were 0.842, 0.796 and 0.728, respectively. CONCLUSIONS: A sensitive and easy photometric
method has been presented. When cobalamin deficiency is suspected in neuropsychiatric
patients, photometric urinary MMA determination analysis can be the first diagnostic
test used. If the urinary MMA concentration is above the reference value, serum
cobalamin levels can be determined for further diagnosis." [Abstract]
Bjelland I, Tell GS, Vollset SE, Refsum H, Ueland
Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism
in anxiety and depression: the Hordaland Homocysteine Study.
Gen Psychiatry. 2003 Jun;60(6):618-26.
"BACKGROUND: An association between
depression and folate status has been demonstrated in clinical studies, whereas
data are sparse on the relationship between depression and other components of
1-carbon metabolism such as vitamin B12, homocysteine, and the methylenetetrahydrofolate
reductase 677C-->T polymorphism. The relationship between anxiety and these
components is less well known. This study examined the associations between folate,
total homocysteine, vitamin B12, and the methylenetetrahydrofolate reductase 677C-->T
polymorphism, and anxiety and depression in a large population-based study. METHODS:
Anxiety and depression, measured by the Hospital Anxiety and Depression Scale,
were assessed in 5948 subjects aged 46 to 49 years (mean, 47.4 years) and 70 to
74 years (mean, 71.9 years) from the Hordaland Homocysteine Study cohort. By means
of logistic regression models, anxiety and depression scores were examined in
relation to the factors listed above. RESULTS: Overall, hyperhomocysteinemia (plasma
total homocysteine level > or =15.0 micro mol/L [> or =2.02 mg/dL]) (odds
ratio, 1.90; 95% confidence interval, 1.11-3.25) and T/T methylenetetrahydrofolate
reductase genotype (odds ratio, 1.69; 95% confidence interval, 1.09-2.62), but
not low plasma folate or vitamin B12 levels, were significantly related to depression
without comorbid anxiety disorder. Plasma folate level was inversely associated
with depression only in the subgroup of middle-aged women. None of the investigated
parameters showed a significant relationship to anxiety. CONCLUSION: Our results
provide further evidence of a role of impaired 1-carbon metabolism in depression."
MP, Shea TB.
Folate and homocysteine metabolism in neural plasticity
and neurodegenerative disorders.
Trends Neurosci. 2003 Mar;26(3):137-46.
is a cofactor in one-carbon metabolism, during which it promotes the remethylation
of homocysteine -- a cytotoxic sulfur-containing amino acid that can induce DNA
strand breakage, oxidative stress and apoptosis. Dietary folate is required for
normal development of the nervous system, playing important roles regulating neurogenesis
and programmed cell death. Recent epidemiological and experimental studies have
linked folate deficiency and resultant increased homocysteine levels with several
neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's
disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine
in the pathogenesis of psychiatric disorders. A better understanding of the roles
of folate and homocysteine in neuronal homeostasis throughout life is revealing
novel approaches for preventing and treating neurological disorders." [Abstract]
H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM.
B12, folate, and homocysteine in depression: the Rotterdam Study.
J Psychiatry. 2002 Dec;159(12):2099-101.
"OBJECTIVE: The associations
of vitamin B(12), folate, and homocysteine with depression were examined in a
population-based study. METHOD: The authors screened 3,884 elderly people for
depressive symptoms. Subjects with positive screening results had psychiatric
workups. Folate, vitamin B(12), and homocysteine blood levels were compared in
278 persons with depressive symptoms, including 112 with depressive disorders,
and 416 randomly selected reference subjects. Adjustments were made for age, gender,
cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia,
vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related
to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association
with depressive disorders was substantially reduced after adjustment for functional
disability and cardiovascular disease, but for vitamin B(12) this appeared independent.
CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders
may have different underlying mechanisms. Vitamin B(12) may be causally related
to depression, whereas the relation with folate is due to physical comorbidity."
M, Strohle A, Hahn A.
[Age-associated changes in the metabolism of
vitamin B(12) and folic acid: Prevalence, aetiopathogenesis and pathophysiological
Z Gerontol Geriatr. 2004 Apr;37(2):109-35.
increasing number of older people is characteristic for most industrialised nations
and implicates the known psychosocial and economic consequences. Therefore, an
optimal nutrient supply that promotes continuing mental and physical well-being
is particularly important. In this respect, vitamin B(12) and folic acid play
a major role, since deficiency of both vitamins is associated with the pathogenesis
of different diseases such as declining neurocognitive function and atherosclerotic
lesions. Vitamin B(12) and folic acid act as coenzymes and show a close molecular
interaction on the basis of the homocysteine metabolism. In addition to the serum
concentrations of the vitamins, the metabolites homocysteine and methylmalonic
acid are sensitive markers of cobalamin and folate status. Depending on the used
marker, 3-60% of the elderly are classified as vitamin B(12) deficient and about
29% as folate deficient. Predominantly, this high prevalence of poor cobalamin
status is caused by the increasing prevalence of atrophic gastritis type B, which
occurs with a frequency of approximately 20-50% in elderly subjects. Atrophic
gastritis results in declining gastric acid and pepsinogen secretion, and hence
decreasing intestinal digestion and absorption of both B vitamins. This is the
reason why an insufficient vitamin B(12) status in the elderly is rarely due to
low dietary intake. In contrast, folic acid intake among elderly subjects is generally
well below the recommended dietary reference values.Even moderately increased
homocysteine levels or poor folate and vitamin B(12) status are associated with
vascular disease and neurocognitive disorders. Results of a meta-analysis of prospective
studies revealed that a 25% lower homocysteine level (about 3 micromol/L) was
associated with an 11% lower ischemic heart disease risk and 19% lower stroke
risk. It is still discussed, whether hyperhomocysteinemia is causally related
to vascular disease or whether it is a consequence of atherosclerosis. Estimated
risk reduction is based on cohort studies, not on clinical trials. Homocysteine
initiates different proatherogenetic mechanisms such as the formation of reactive
oxygen species and an enhanced fibrin synthesis. Supplementation of folic acid
(0.5-5 mg/d) reduces the homocysteine concentration by 25%. Additional vitamin
B(12) (0.5 mg/d) induces further reduction by 7%. In secondary prevention, supplementation
already led to clinical improvements (reduction of restenosis rate and plaques).Depression,
dementia, and mental impairment are often associated with folate and vitamin B(12)
deficiency. The biochemical reason of this finding may be the importance of folic
acid and vitamin B(12) for the transmethylation of neuroactive substances (myelin,
neurotransmitters) which is impaired in vitamin deficiency ("hypomethylation
hypothesis").In recent years, there is increasing evidence for a role of
folic acid in cancer prevention. As a molecular mechanism of a preventive effect
of folic acid the hypomethylation of certain DNA sections in folate deficiency
has been suggested. Since folate and vitamin B(12) intake and status are mostly
insufficient in elderly subjects, a supplementation can generally be recommended."
MS, Fava M, Jacques PF, Selhub J, Rosenberg IH.
Depression and folate
status in the US Population.
Psychother Psychosom. 2003
"BACKGROUND: Folate deficiency and low folate status
have been linked in clinic studies to depression, persistent depressive symptoms,
and poor antidepressant response. These relationships have not been demonstrated
in general populations. This study examined associations between depression and
folate status indicators in an ethnically diverse general US population sample
aged 15-39 years. METHODS: Healthy subjects whose red blood cell (RBC) folate
concentrations had been measured were determined to have no depression (n = 2,526),
major depression (n = 301), or dysthymia (n = 121) using a diagnostic interview
schedule. Serum concentrations of folate and total homocysteine (tHcy) were also
measured. RESULTS: After adjustment for sociodemographic factors, serum vitamin
B(12) concentration, alcohol consumption over the past year and current status
as to overweight and use of vitamin/mineral supplements, cigarettes and illegal
drugs, subjects who met criteria for a lifetime diagnosis of major depression
had folate concentrations in serum and RBCs that were lower than those of subjects
who had never been depressed. Subjects who met criteria for dysthymia alone had
lower RBC folate concentrations than never-depressed subjects, but the serum folate
concentrations of the two groups were comparable. Serum tHcy concentration was
not related to lifetime depression diagnoses. Low folate status was found to be
most characteristic of recently recovered subjects, and a large proportion of
such subjects were folate deficient. CONCLUSIONS: Low folate status was detectable
in depressed members of the general US population. Folate supplementation may
be indicated during the year following a depressive episode." [Abstract]
Tolmunen, Tommi, Voutilainen, Sari, Hintikka, Jukka, Rissanen,
Tiina, Tanskanen, Antti, Viinamaki, Heimo, Kaplan, George A., Salonen, Jukka T.
Folate and Depressive Symptoms Are Associated in Middle-Aged Finnish Men
Nutr. 2003 133: 3233-3236
"Several cross-sectional studies have focused
on the low blood folate levels of depressed patients. However, no published studies
have examined the association between dietary folate and current symptoms of depression
in a general population. We investigated the association between dietary folate,
cobalamin, pyridoxine and riboflavin and current symptoms of depression in a cross-sectional
general population study. We recruited 2682 men aged between 42 and 60 y from
eastern Finland. Those who had a previous history of psychiatric disorder were
excluded (n = 146, 5.6% of the cohort). Depressive symptoms were assessed with
the 18-item Human Population Laboratory Depression Scale. Those who scored 5 or
more at baseline were considered to have elevated depressive symptoms (n = 228,
9.3% of the cohort). The participants were grouped into thirds according to their
dietary folate intake. Those in the lowest third of energy-adjusted folate intake
had a higher risk of being depressed [odds ratio (OR) 1.67, 95% CI = 1.19-2.35,
P = 0.003] than those in the highest folate intake third. This increased risk
remained significant after adjustment for smoking habits, alcohol consumption,
appetite, BMI, marital status, education, adulthood socioeconomic status and total
fat consumption (OR = 1.46, 95% CI = 1.01-2.12, P = 0.044). There were no associations
between the intake of cobalamin, pyridoxine or riboflavin, and depression. These
results indicate that nutrition may have a role in the prevention of depression."
MW, Chary TK, Laundy M, Bottiglieri T, Chanarin I, Reynolds EH, Toone B.
cell folate concentrations in psychiatric patients.
Disord. 1990 Jul;19(3):207-13.
"Red cell folate and vitamin B12 estimations
were performed on 243 successively admitted in-patients at a District General
Hospital Psychiatric Unit and 42 out-patients (29 attending a lithium clinic).
Patients were classified into five diagnostic groups. The mean ages of the manic
and schizophrenic patients were lower than of the depressed or euthymic patients
but age was not correlated with red cell folate or serum B12 levels in any group.
There were 89 (31%) patients with red cell folate below 200 ng/ml and 35 (12%)
with concentrations below 150 ng/ml. Significantly more of these low-folate patients
were in-patients than out-patients. The mean red cell folate in the depressed
patients was significantly lower than in the euthymic, manic and schizophrenic
groups. Alcoholics had a similar mean red cell folate to depressed patients which
was not quite significantly lower than the other groups. The mean serum B12 level
in the alcoholics was, however, significantly raised. There were no significant
differences in red cell folate or serum B12 between lithium-treated and untreated
euthymic patients. The highest proportions of values below 200 ng/ml and 150 ng/ml
were found in depressed and alcoholic patients. Endogenous depressives had the
highest percentage of values below 150 ng/ml (folate-deficient) of all psychiatric
groups and alcoholic patients." [Abstract]
Wolfersdorf M, Konig F.
acid and vitamin B12 in depressed inpatients. A study of serum folic acid with
radioimmunoassay in 121 depressed inpatients]
Prax. 1995 Jul;22(4):162-4.
"According to the newer literature on folate
deficiencies in depressive patients serum folate and vitamin B12 levels were studied
(RIA) in 121 consecutively admitted depressive inpatients (47 male, 74 female
depressives; age 17-86 years, mean age 48 years, diagnostic by ICD-9 300.4, 296.1)
during the first (1-3) days of admission (normal volumes folate 3-17 ng/ml, vitamin
B12 200-900 pg/ml). Only in two patients serum folate below 3 ng/ml were found,
low vitamin B12 levels (below 200 pg/ml) showed 14 patients. This result is in
contrast to other authors who found folate deficiencies in 10-50% of psychiatric
A, Garcia-Unzueta MT, Amado JA, Lopez-Cordovilla JJ, Diez-Manrique JF, Vazquez-Barquero
Folate levels in psychiatric outpatients.
Clin Neurosci. 1999 Aug;53(4):531-3.
"This study examines folate in psychiatric
outpatients. Fifty-three outpatients with schizophrenia and 24 outpatients with
depressive disorder assessed with the Schedules for Clinical Assessment in Neuropsychiatry
interview are included. Patients with schizophrenia had lower serum folate levels
than age- and sex-matched controls, while red cell folate levels did not differ.
Serum folate levels showed a negative correlation with the Clinical Global Impression,
disorganized dimension, and total Positive and Negative Syndrome Scale score.
Patients with depressive disorder had lower serum folate levels than healthy controls,
but showed no differences in red cell folate levels. Only two patients with schizophrenia
had red cell folate levels below the normal range." [Abstract]
MT, Coppen A.
Serum and red blood cell folate in depression.
Psychiatr Scand. 1989 Jul;80(1):78-82.
"Serum folate concentrations were
estimated in patients with major depressive disorders, lithium-treated patients,
detoxified alcoholic patients and normal controls. Red blood cell (RBC) folate
concentrations were also estimated in subgroups of patients with major depressive
disorder and normal controls. Results showed significantly lower serum and RBC
folate concentrations in patients with major depressive disorder than in normal
controls. Lower serum folate concentrations were associated with greater severity
of depression. There was no association between serum and RBC folate concentrations
and endogenicity of depression or the presence of weight loss." [Abstract]
AJ, Joffe RT.
Folate, B12, and life course of depressive illness.
Psychiatry. 1989 Apr 1;25(7):867-72.
"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." [Abstract]
M, Silva RR, Pouget ER.
Prediction of treatment response in geriatric
depression from baseline folate level: interaction with an SSRI or a tricyclic
J Clin Psychopharmacol. 2003 Jun;23(3):309-13.
geriatric patients have lower levels of folate (FOL) than controls. Also, FOL
supplement can reduce depressive morbidity. One hypothesis consistent with this
is that FOL deficiency causes a lowering of CNS serotonin that contributes to
depression. The present report is from one site of a multicenter study that compared
an SSRI (sertraline) with a nonspecific tricyclic antidepressant (nortriptyline)
in geriatric depressed patients. We added measures of FOL at baseline and outcome
for 22 depressed patients older than 60 years. Both treatments were effective.
At baseline, FOL levels were within the normal range. Higher FOL levels at baseline
predicted greater improvement. Further study of FOL interaction with SSRI is warranted.
For the group treated with the SSRI, baseline FOL level was a more efficient predictor
of improvement, especially for results on a self-rating depression scale (POMS)."
IR, Edman JS, Morrow FD, Marby DW, Mirages S, Perrone G, Kayne HL, Cole JO.
complex vitamin patterns in geriatric and young adult inpatients with major depression.
Am Geriatr Soc. 1991 Mar;39(3):252-7.
"This study compared the B complex
vitamin status at time of admission of 20 geriatric and 16 young adult non-alcoholic
inpatients with major depression. Twenty-eight percent of all subjects were deficient
in B2 (riboflavin), B6 (pyridoxine), and/or B12 (cobalamin), but none in B1 (thiamine)
or folate. The geriatric sample had significantly higher serum folate levels.
Psychotic depressives had lower B12 than did non-psychotic depressives. Poorer
blood vitamin status was not associated with higher scores on the Hamilton Depression
Rating Scale or lower scores on the Mini-Mental State Examination in either age
group. The data support the hypothesis that poorer status in certain B vitamins
is present in major depression, but blood measures may not reflect central nervous
system vitamin function or severity of affective syndromes as measured by the
assays and scales in the present study." [Abstract]
BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP.
B(12) deficiency and depression in physically disabled older women: epidemiologic
evidence from the Women's Health and Aging Study.
Am J Psychiatry.
"OBJECTIVE: It has been hypothesized that adequate
concentrations of vitamin B(12) and folate are essential to maintain the integrity
of the neurological systems involved in mood regulation, but epidemiologic evidence
for such a link in the general population is unavailable. This study examined
whether community-dwelling older women with metabolically significant vitamin
B(12) or folate deficiency are particularly prone to depression. METHOD: Serum
levels of vitamin B(12), folate, methylmalonic acid, and total homocysteine were
assayed in 700 disabled, nondemented women aged 65 years and over living in the
community. Depressive symptoms were measured by means of the Geriatric Depression
Scale and categorized as no depression, mild depression, and severe depression.
RESULTS: Serum homocysteine levels, serum folate levels, and the prevalences of
folate deficiency and anemia were not associated with depression status. The depressed
subjects, especially those with severe depression, had a significantly higher
serum methylmalonic acid level and a nonsignificantly lower serum vitamin B(12)
level than the nondepressed subjects. Metabolically significant vitamin B(12)
deficiency was present in 14.9% of the 478 nondepressed subjects, 17. 0% of the
100 mildly depressed subjects, and 27.0% of the 122 severely depressed women.
After adjustment for sociodemographic characteristics and health status, the subjects
with vitamin B(12) deficiency were 2.05 times as likely to be severely depressed
as were nondeficient subjects. CONCLUSIONS: In community-dwelling older women,
metabolically significant vitamin B(12)deficiency is associated with a twofold
risk of severe depression." [Abstract]
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.
study evaluated the relationships between normal serum vitamin B12 and folate
levels and neuropsychologic measures in a sample of 60 geriatric inpatients with
psychotic depression, nonpsychotic depression, bipolar disorder, and dementia--all
consecutively referred for cognitive testing. The psychotic depression subgroup
demonstrated numerous significant positive correlations between B12 and cognitive
subtests not seen in other diagnostic subgroups, especially those of IQ, and verbal
and visual memory. Metabolic factors including vitamin B12 may play specific roles
in the cognitive dysfunctions of different geropsychiatric disorders." [Abstract]
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
Biol Psychiatry. 1990 Jan 15;27(2):125-37.
chart review study examined the serum vitamin B12 and folate status of 102 geriatric
patients newly admitted to a private psychiatric hospital. Only 3.7% were B12
deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those
with below-median values of both vitamins had significantly lower Mini-Mental
State scores than patients higher in one or both vitamins. Patients with "organic
psychosis" with a negative family history for psychiatric disorder had significantly
lower B12 levels than those with a positive family history. In major depression,
folate levels correlated negatively with age at onset of psychiatric illness and
length of hospitalization. These data suggest that (1) biochemically interrelated
vitamins such as B12 and folate may exert both a separate and a concomitant influence
on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric
disorders that begin at a later age and lack a familial predisposition."
IR, Edman JS, Morrow FD, Marby DW, Perrone G, Kayne HL, Greenwald M, Cole JO.
communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant
treatment in geriatric depression with cognitive dysfunction.
Am Coll Nutr. 1992 Apr;11(2):159-63.
"This was a 4-week randomized placebo-controlled
double-blind study to assess augmentation of open tricyclic antidepressant treatment
with 10 mg each of vitamins B1, B2, and B6 in 14 geriatric inpatients with depression.
The active vitamin group demonstrated significantly better B2 and B6 status on
enzyme activity coefficients and trends toward greater improvement in scores on
ratings of depression and congnitive function, as well as in serum nortriptyline
levels compared with placebo-treated subjects (Ss). Without specific supplementation,
B12 levels increased in Ss receiving B1/B2/B6 and decreased in placebo Ss. These
findings offer preliminary support for further investigation of B complex vitamin
augmentation in the treatment of geriatric depression." [Abstract]
F, Thalassinos M, Miller HD, Lemperiere T.
Folates and post partum
J Affect Disord. 1992 Aug;25(4):235-41.
can cause psychiatric disturbances of a depressive nature. Pregnancy and delivery
are often associated with hypofolatemia. This study was conducted to determine
if hypofolatemia at day 3 post partum is a risk factor for baby blues or post
partum depression. To study this hypothesis, 131 post partum women were followed
prospectively for the 3 months immediately following delivery. 19% were found
to have 'baby blues', as defined by a score greater than 20 on Pitt's scale (Pitt,
1968, J. Psychiatry 114, 1325-1335) and 12% had post partum depression as defined
by a score greater than 7 on QD2A scale (Pichot et al., 1984, Rev. Psycholog.
App. 34, 229-250, 323-340), within the three months post partum. No relationship
was observed between the serum or erythrocyte folate levels on the third day following
delivery and the maternal post partum depression scores. A statistically significant
correlation between post partum depression and previous psychiatric disturbance
was, however, observed." [Abstract]
TT, Goodkin K, Blaney NT, Shor-Posner G, Kumar M, Wilkie FL, Baum MK, Eisdorfer
Cobalamin level is related to self-reported and clinically rated
mood and to syndromal depression in bereaved HIV-1(+) and HIV-1(-) homosexual
J Psychosom Res. 2000 Feb;48(2):177-85.
An examination of the relationship of plasma cobalamin (vitamin B(12)) level to
overall psychological distress, specific mood states, and major depressive disorder
was conducted in 159 bereaved men (90 HIV-1(+) and 69 HIV-1(-)). METHODS: The
relationship of a continuous measure of cobalamin level to psychological distress
was examined, while controlling for HIV-1 serostatus, life stressors, social support,
and coping styles. RESULTS: Of this sample, 23.9% were either overtly or marginally
cobalamin deficient; however, the deficiency rate was not significantly different
by HIV-1 serostatus. Cobalamin level was inversely related to self-reported overall
distress level and specifically to depression, anxiety, and confusion subscale
scores, as well as to clinically rated depressed and anxious mood. Lower plasma
cobalamin levels also were associated with the presence of symptoms consistent
with major depressive disorder. CONCLUSION: These findings suggest that cobalamin
level may be physiologically related to depressed and anxious mood level, as well
as to syndromal depression." [Abstract]
DO, Stern RA, Golden RN, Murphy C, Naftolowitz D, Evans DL.
disorders in HIV infection: prevalence and risk factors in a nonepicenter of the
Am J Psychiatry. 1994 Feb;151(2):233-6.
These findings are in agreement with previous studies of areas with a high prevalence
of HIV. However, the proportion of subjects with mood disorders is high compared
with general population studies. Both HIV-infected and uninfected homosexual men
may be at high risk for major depression, especially if they have a past history
of depression. Moreover, in the asymptomatic stage of HIV infection, major depression
does not appear to be secondary to HIV central nervous system effects or low vitamin
B12 levels." [Abstract]
KA, Bulik CM, Joyce PR.
Visceral protein and hematological status
of women with bulimia nervosa and depressed controls.
Behav. 1999 Mar;66(1):159-63.
"Serum visceral protein and hematological
indices and their behavioral and clinical correlates were determined in women
with bulimia nervosa and depressed controls. One hundred and fifty-two women who
met DSM-IV criteria for bulimia nervosa and 68 women with DSM-IV major depression
completed a structured clinical interview and had blood samples drawn prior to
admission to outpatient treatment programs. Albumin and prealbumin concentrations
were lower in the depressed women, possibly due to recent weight loss. Elevated
transferrin values suggested mild iron deficiency in nearly one-fifth of women
with bulimia nervosa. Of women with bulimia nervosa, the 10.7% who had hemoglobin
and 5.1% who had vitamin B12 levels below the normal range were not distinguishable
on measures of body mass index, binge eating, vomiting, or restriction frequency.
The 4.3% with low prealbumin levels experienced significantly more episodes of
binge eating and vomiting in the prior fortnight than those with normal values.
Frequency of vomiting was also inversely associated with albumin concentration.
Hamilton Depression Rating Scale scores were inversely and linearly related to
serum vitamin B12. Lower B12 levels in those with alcohol abuse/dependence did
not explain the association between B12 and HDRS scores. No hematological indices
were related to body mass index, binge eating or restriction frequency, or restriction
intensity. In summary, women with bulimia nervosa do not appear to be at greater
risk of visceral protein or hematological abnormalities than psychiatric controls.
It is suggested that a high frequency of vomiting and alcohol abuse/dependence,
increases the risk of subclinical malnutrition in women with bulimia nervosa,
and that poor vitamin B12 nutriture may interfere with the functioning of the
serotonergic or catecholaminergic systems and contribute to depressive symptoms
in bulimia nervosa." [Abstract]