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Effect of Folic Acid Combined with Fluoxetine in Patients with Major Depression on Plasma Homocysteine and Vitamin B12, and Serotonin Levels in Lymphocytes

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Objective(s): Folic acid, a micronutrient supporting the natural defense system, may elevate antidepressant responses, although the lymphocyte serotonergic system has not been explored in folate-supplemented depressed patients. Methods: Twenty-seven patients were randomly assigned to groups receiving fluoxetine (20 mg) and folic acid (10 mg/day) or fluoxetine and placebo for 6 weeks. Clinical outcome was assessed according to the Hamilton Depression Rating Scale (HDRS) at the beginning, during and at the end of treatment. Blood samples were taken, plasma was separated, and lymphocytes were obtained by density gradient centrifugation with Ficoll/Hypaque and differential adhesion to plastic dishes. Fifteen healthy subjects served as controls. Plasma folate, homocysteine and vitamin B12, and serotonin concentration in lymphocytes were determined by HPLC. The HDRS score was significantly lower in patients receiving fluoxetine and folic acid compared with those receiving fluoxetine and placebo after 6 weeks of treatment (7.43 +/- 1.65 vs. 11.43 +/- 1.31, respectively; p = 0.04). Plasma homocysteine statistically significant decreased after folic acid (p = 0.02), but no significant changes were observed in vitamin B12. Results: Serotonin was significantly reduced after fluoxetine either with folate (p = 0.03) or placebo (p = 0.01) probably by the effect of transporter blockade. 5-Hydroxyindoleacetic acid was lower in lymphocytes of patients receiving folate (p = 0.04), indicating a reduced turnover rate, thus accumulating serotonin in the cells. A significant negative correlation was noted between homocysteine and folate. No significant correlations were present among biochemical parameters and depression severity. Conclusion: Modifications due to treatment with fluoxetine and folic acid may alter lymphocyte function in depression probably indirectly by reducing homocysteine levels and directly on lymphocytes by modifying the serotonergic system.
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Original Paper
Neuroimmunomodulation 2008;15:145–152
DO I: 10 .1159/0 00151527
Effect of Folic Acid Combined with Fluoxetine
in Patients with Major Depression on Plasma
Homocysteine and Vitamin B
12
, and Serotonin
Levels in Lymphocytes
G u s t a v o R e s l e r
a
Renée Lavie
a
Julio Campos
a
Salvador Mata
a
Mary Urbina
b
Alberto García
c
Rafael Apitz
c
Lucimey Lima
b
a Servicio de Psiquiatría, Hospital Vargas de Caracas, y
b Laboratorio de Neuroquímica, y
c Laboratorio de
Trombosis Experimental, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas,
Caracas , Venezuela
score was significantly lower in patients receiving fluoxetine
and folic acid compared with those receiving fluoxetine and
placebo after 6 weeks of treatment (7.43 8 1.65 v s. 11.43 8
1.31, respectively; p = 0.04). Plasma homocysteine statisti-
cally significant decreased after folic acid (p = 0.02), but no
significant changes were observed in vitamin B
12
. Results:
Serotonin was significantly reduced after fluoxetine either
with folate (p = 0.03) or placebo (p = 0.01) probably by the
effect of transporter blockade. 5-Hydroxyindoleacetic acid
was lower in lymphocytes of patients receiving folate (p =
0.04), indicating a reduced turnover rate, thus accumulating
serotonin in the cells. A significant negative correlation was
noted between homocysteine and folate. No significant cor-
relations were present among biochemical parameters and
depression severity. Conclusion: Modifications due to treat-
ment with fluoxetine and folic acid may alter lymphocyte
function in depression probably indirectly by reducing ho-
mocysteine levels and directly on lymphocytes by modify-
ing the serotonergic system. Copyright © 20 08 S. Karger AG, Basel
Key Words
Folic acid Fluoxetine Homocysteine Ly mphocytes
Major depression Serotonin
A b s t r a c t
O b j e c t i v e ( s ) : Folic acid, a micronutrient supporting the nat-
ural defense system, may elevate antidepressant responses,
although the lymphocyte serotonergic system has not been
explored in folate-supplemented depressed patients. Meth-
ods: Twenty-seven patients were randomly assigned to
groups receiving fluoxetine (20 mg) and folic acid (10 mg/
day) or fluoxetine and placebo for 6 weeks. Clinical outcome
was assessed according to the Hamilton Depression Rating
Scale (HDRS) at the beginning, during and at the end of treat-
ment. Blood samples were taken, plasma was separated, and
lymphocytes were obtained by density gradient centrifuga-
tion with Ficoll/Hypaque and differential adhesion to plastic
dishes. Fifteen healthy subjects served as controls. Plasma
folate, homocysteine and vitamin B
12
, and serotonin concen-
tration in lymphocytes were determined by HPLC. The HDRS
Re ceived: January 25, 200 8
Accepted afte r revision: May 9, 2008
Published o nline: August 21, 2008
Dr. Lucimey Lima
Laborator io de Neuroquímic a, Centro de Biofísica y Bioquím ica
Instituto Venezolano de Investigaciones Científ icas
Apdo. 21827, Caracas 1020 -A (Venezuela)
Tel. +58 212 504 1213, Fax +58 212 504 1295, E-Mail lli ma@ivic.ve
© 20 08 S. Karger AG, Bas el
1021–7401/08/0153–0145$24.50/0
Accessible online at:
www.karger.com/nim
Resler /Lavie /Campos /Mata /Urbina /
García
/Api tz /Lima
Neuroimmunomodulation 2008;15:145–152
146
Introduction
The administration of vitamins and other natural
stimulants for the treatment of depressive symptoms has
been common practice for several years. Physicians ob-
served empirically the clinical improvement without
knowledge of the underlying biological mechanisms
[1] .
More recently, vitamins have been found to act as cofac-
tors of enzymatic reactions, drawing attention to their
involvement in various diseases, e.g. in psychiatric disor-
ders
[2–5] .
Major depressive disorders are one of the main causes
of d isability in the world, with significant negative socio-
economic consequences
[6, 7] . Based on the theory ex-
plaining mood disorders, especially depression, with im-
balanced biogenic amine synthesis, e.g. serotonin (5-HT)
and catecholamines, and ascribing folic acid the role of
an indirect cofactor, it is reasonable to think that their
supplementation could result in increased neurotrans-
mitter synthesis and thus improve the clinical response
to antidepressant treatment
[3, 4, 8–14] .
In humans, fruits and vegetables constitute the pri-
mary nutritious source of folate, with a recommended
daily intake of 400 g, but this requirement is elevated
during periods of high metabolic demand, for example in
pregnancy
[15, 16] . Tetrahydrofolate (THF) is transport-
ed to the cell interior by a specific transporter, and the
safety of daily supplements of 5–15 mg folic acid has been
reported
[17 ] .
The main function of folic acid is to trigger biochemi-
cal reactions to transfer 1-carbon group of methyl and
formyl. Serine is the main source of these groups reacting
with THF to produce glycine and N-5,10-methylene-
THF. These by-products constitute a source of carbon
group donors tr ansfe rring it to a n appropr iate receptor to
form metabolic intermediates and finally precursors for
de novo synthesis of macromolecules, e.g. purines, de-
oxythymidylate monophosphate and methionine. The
latter is formed by the transfer of the methyl group from
N-5-methyl-THF to form methyl-homocysteine. Folate
deficiency restricts the methylation of homocysteine to
methionine, a reaction which needs vitamin B
12 [18 , 19] .
In vit ro studies have revealed that folate deficiency in-
creases the risk of depression
[11, 14, 20] . Folate metabo-
lism is linked to biopterin-dependent neurotransmitter
synthesis, to biogenic amine methylation and to phos-
pholipid synthesis in the central nervous system
[5, 18] .
Homocysteine or its metabolites have excitotoxic effects
through glutamate N-methyl-
D -aspartate receptors or by
the inhibition of S-adenosyl-methionine-dependent bio-
genic amine methylation and the formation of S-adeno-
syl-homocysteine. Some authors proposed that S-adeno-
syl-methionine could be superior to placebo in the treat-
ment of depression
[20] .
Pauling [21] presented the hypothesis that many men-
tal illnesses are due to insufficient concentrations of cere-
bral cofactors as a result of an insufficient consumption
of micronutrients and that some cerebral dysfunctions
may be due to mutations that affect the affinity constant
of the enzyme substrates. For instance, the polymorphism
677C ] T of methylene-THF reductase has been exam-
ine d in p atient s w ith s chiz ophr enia , major dep ress ive di s-
orders and bipolar disorders. The TT gene variant of the
methylene-THF reductase was found in 12% of 419 healthy
controls, 21% of 297 patients with schizophrenia, 28% of
32 patients with major depression and 13% of 40 patients
with bipolar disorders
[22] . Melancholic depressions oc-
cur more often in subjects with decreased levels, having a
bad response to fluoxetine administration
[2, 3, 12, 14,
18]
. Recently, the relationship between folate and depres-
sion has been considered a neglected problem
[23] .
For the above reasons and the lack of information on
cellular peripheral 5-HT in folate-supplemented pa-
tients, the main objective of the present work was to ex-
plore possible modifications in 5-HT turnover in lym-
phocytes induced by folic acid supplementation which
may be related to its immune function. In addition, sec-
ondary aims were: (1) to study the effect of folic acid ad-
ministration on the antidepressant response to fluox-
etine, and (2) to determine plasma levels of folate, homo-
cysteine and vitamin B
12
before and after 6 weeks of
treatment, in order to correlate these parameters with
the severity of depression.
Patients and Methods
From 76 patients consulting for depression at the Servicio de
Psiquiatría, Hospital Vargas de Caracas, from May to December
2006, 27 outpatients (23 women and 4 men) (21–58 years old,
35.04 8 2 .63) recently dia gnosed with a major depressive epis ode,
in the absence of other psychiatric or medical conditions, and
without psychotic symptoms or risk of suicide were studied. Pa-
tients treated with any antidepressant or vitamin during the 30
days prior to study entry were excluded. Each patient was in-
formed about the aims and implications of the study and was re-
quested to sign an informed consent according to the Ethic Com-
mittees of the Hospital and the Institute. Diagnosis was estab-
lished usi ng the clinica l version (SCID-I) of the depression sec tion
of the Structured Clinical Interview for Axis I Disorders (Spanish
version) of the Diagnostic and Statistical Manual of Mental Dis-
orders (DSM-IV)
[24] . This questionnaire is supported by the di-
Effect of Folic Acid Supplementation on
Major Depression
Neuroimmunomodulation 2008;15:145–152
147
agnost ic criteria for major depression of the America n Psychiatric
Association (DSM-IV)
[25] . The clinical severity of depressive
symptoms was assessed at the beginning and every other week (0,
3 and 6 weeks) using the 17-item Hamilton Depression Rating
Scale (H DRS)
[26] , validated i n Spain, in which a score 6 18 po int s
suggests mild, moderate or severe episodes
[27] . A 50% reduction
in the HDRS score with respect to the basal score was considered
as response
[28] . The control group was composed of 15 appar-
ently healthy subjects (9 women and 6 men; 26–49 years old,
mean: 34.13 8 2.05) without any personal or family history of
psychiatric diseases. According to the modified Graffar classifi-
cation, all subjects belonged to class III (low middle class) or IV
(worki ng cla ss)
[29] . Consumption of caffeine was moderate
(maximally two small cups per day), alcohol occasional and to-
bacco sporadic in a few of them.
Patients were randomly assigned to two groups in a blind
manner using a lottery procedure. One of the two groups com-
prised 14 individuals, who received 20 mg/day of fluoxetine plus
10 mg of folic acid during 6 weeks, while the second group, 13 pa-
tients, was treated with 20 mg of fluoxetine plus placebo during
the same t ime period. Fluoxeti ne was given in the form of g rooved
tablets of 20 mg of fluoxetine hydrochloride. Folic acid and pla-
cebo were administered as gelatin capsules containing 10 mg of
the vitamin
[2] or a similar quantity of inert powder. They were
provided by the physician every 2 weeks in plastic bags prepared
by non-medical personal and containing the exact amount to be
taken during that period of time.
Folic Acid, Homocysteine and Vitamin B
12
Determination in
Plasma
The determinations were performed at the beginning (day 0)
and at the end of the study (week 6). The samples were labeled by
continuous numeration for blindness of biochemical perfor-
mance and calculations. Peripheral vein blood was sampled be-
tween 7 and 8 a.m. and collected in a BD Vacutainer tube with
heparin as anticoagulant (1,000 U/ml). After centrifugation at
1,500 g , plasma was obtained and further centrifuged at 4
° C,
38,000 g , for 10 min to obtain platelet-poor plasma. The samples
were frozen at –80
° C until assayed. Folic acid, homocysteine and
vitamin B
12
were determined by high-performance reverse-phase
liquid chromatography (HPLC), as previously described
[30] .
Serotonin and 5-Hydroxyindoleacetic Acid in Lymphocytes
Blood (20 ml) was centrifuged at 500 g with a vasculant rotor
for 10 min at room temperature. The layer of white plus some red
blood cells was taken and transferred to tubes with 0.1
M phos-
phate-buffered saline solution (PBS, pH 7.4) and centrifuged at
160 g for 10 min at room temperature. The white layer was col-
lected, suspended in 10 ml of PBS, placed on 5 ml of Ficoll/
Hypaque (1,077 g/l) and, af ter centrifugat ion at 1,500 g for 30 min,
peripheral blood mononuclear cells were collected and placed on
plastic tissue culture dishes to obtain nonadherent lymphocytes
(85 8 5% CD3+). Cells were counted in a hemocytometer and
di lut ed i n R PMI 1640 to rea ch a spe cifi c ce ll c onc ent rat ion . In teg-
rity of the membrane was determined by trypan blue dye exclu-
sion (viability 6 96%)
[31] . The cells were suspended in HPLC
buffer solution, homogeni zed in Tissumiz er (Tekmar, Cincinnat i,
Ohio, USA) and centrifuged at 38,000 g for 10 min; the superna-
tant was analyzed for 5-HT and 5-hydroxyindoleacetic acid (5-
HIAA). The system was composed of an integrator and a pump
(Waters HPLC model 600; Waters, Minnesota, USA), an auto-
matic injector (Waters model 7171), a Supelco LC-18 column (15
cm ! 4.6 mm inside diameter, average particle size: 5 m) and
an electrochemical detector (Waters model 464; +0.7 V, 0.2 nA).
The mobile phase was 0.02
M sodium acet ate, 0.0125 M citric acid,
1 m
M EDTA, 1.52 m M octanyl sulfonate, pH 3.9, plus 10% aceto-
nitri le
[31] . The a mount present in the sample was ca lculated from
the area under the curve of samples and external standards with
the program Millenium (Waters). Concentrations are expressed
in nanograms per 10
6
cells.
Statistical Analysis
At the end of the study, the identification of patients with cor-
responding samples was done for performing corresponding
analy sis. Data were expressed a s means 8 SEM, and p ^ 0.05 was
considered statistically significant with a confidence interval of
95%. Data before treatment and differences between groups were
analyzed using Student’s t test. The nonparametric Mann-Whit-
ney U test was utilized to analyze treatment effects. Linear cor-
relation ana lysis was performed b etween parameters a nd between
parameters and severity of depression. The data were classified
and analyzed using the Statistical Package for Social Sciences
(SPSS, Chicago, Ill., USA).
R e s u l t s
P a t i e n t s
Depressive patients with concomitant medical illness-
es, e.g. hypertension, diabetes or allergies, were not in-
clu de d i n t he pr es en t s tu dy. Twe nt y of t he 27 pa ti en ts co m-
0
5
10
15
20
25
HDRS score
024
Placebo
Folic acid
6
*
Weeks of treatment
F i g . 1 . Mean HDRS scores at the beginning, and 2, 4 and 6 weeks
after t reatment with f luoxetine (20 mg/day) and placebo, or f luox-
etine (20 mg/day) and folic acid (10 mg/day) * p ! 0.05 vs. place-
bo.
Resler /Lavie /Campos /Mata /Urbina /
García
/Api tz /Lima
Neuroimmunomodulation 2008;15:145–152
148
pleted the 6-week study; the remainder abandoned the
study but reported partia l amelioration of symptoms after
3–4 weeks of treatment, with a 30% reduction in the
HDRS score. Main symptoms were sadness, anhedonia,
anorexia, insomnia and anxiety. No side effects were re-
ported by this group of patients. At the beginning of the
study, the median HDRS scores were 22.50 8 0.98 for the
folate group and 21.85 8 0.94 for the placebo group (p =
0.32). At the end of the study (week 6), both groups pre-
sented clinical improvement, with a statistically signifi-
cant decline in the HDRS score in both groups ( fig. 1 ). The
average final HDRS scores were 7.43 8 1.65 for the folate
group and 11.43 8 1.31 for the placebo group (p = 0.04).
Plasma Levels of Folic Acid, Homocysteine and
Vitamin B
12
There were no significant differences in the plasma
folate concentrations between the groups at the begin-
ning of the study. Folate concentration was markedly in-
creased in the folate-supplemented group, with values of
9.22 8 1.97 to 47.81 8 6.66 n
M (p = 0.0005) versus 9.10
8 1.66 and 11.61 8 3.53 n
M in the placebo group (non-
significant), but the 6-week folate concentration was sig-
nificantly lower in the placebo group compared with the
folate-supplemented group (p = 0.0006; fig. 2 ). The dif-
ference in plasma homocysteine concentrations among
the groups at study entry was not statistically significant
0
10
20
30
40
50
60
Folic acid (n )
M
Placebo Folic acid Control
Before
After *
0
2
4
8
10
12
14
Homocysteine (µ )
M
Placebo Folic acid Control
Before
After
*
6
0
400
200
600
800
1,200
1,400
Vitamin B (p )
12 M
Placebo Folic acid Control
Before
After
1,000
F i g . 2 4 . Folic acid ( 2 ), homocysteine ( 3 ) and vitamin B
12
concen-
trations (
4 ) in t he plasma of the control group and i n the depressed
patients treated with fluoxetine (20 mg/day) and placebo, or
fluoxetine (20 mg/day) and folic acid (10 mg/day) for 6 weeks.
Plasma was obtained before treatment initiation and at the end of
week 6. * p ! 0.05 vs. before.
2 3
4
Effect of Folic Acid Supplementation on
Major Depression
Neuroimmunomodulation 2008;15:145–152
149
(9.49 8 0.7 p M) . However, levels were significantly de-
creased in the folate group at study completion (7.35 8
0.61 p
M; p = 0.02; fig. 3 ). Vitamin B
12
demonstrated intra-
and intergroup variations, but no statistically significant
differences were found ( fig. 4 ).
5-HT and 5-HIAA Concentrations in Lymphocytes
5-HT did not significantly differ among the placebo,
folic acid or control groups. The administration of fluox-
etine with (p = 0.03) or without (p = 0.01) folate supple-
mentation reduced the 5-HT concentration in lympho-
cytes ( fig. 5 a). 5-HIAA was not significantly different
between the patients and the controls; however, the me-
tabolite was markedly decreased in the folate-supple-
mented group (p = 0.04; fig. 5 b). The 5-HT/5-HIAA ratio
was lower in depressed patients; however, there was a
wide variation in the control group, with no effect of
treatment ( fig. 5 c).
Discussion
The majority of patients included in this study were
female, in agreement with epidemiological findings on
a worldwide basis indicating that the number of women
diagnosed with depressive disorders surpasses that of
0
500
1,500
2,000
3,000
4,000
5,000
Placebo Folic acid Control
Before
After
*
1,000
2,500
4,500
3,500
*
5-HT (pg/10 cells)
6
a0
100
200
300
400
500
600
Placebo Folic acid Control
Before
After
*
5-HIAA (pg/10 cells)
6
b
0
20
40
60
80
100
120
5-HT/5-HIAA
Placebo Folic acid Control
Before
After
c
F i g . 5 . Concentrations of 5-HT ( a ) and 5-HIAA ( b ), and 5-HT/5-
HIAA ratio (
c ) in lymphocytes of the control group and in the
depressed patients treated with fluoxetine (20 mg/day) and pla-
cebo, or fluoxetine (20 mg/day) and folic acid (10 mg/day) for 6
weeks. * p ! 0.05 vs. corresponding value before treatment.
Resler /Lavie /Campos /Mata /Urbina /
García
/Api tz /Lima
Neuroimmunomodulation 2008;15:145–152
150
men and that women are more comfortable seeking help
[32, 33] . The severity of depressive symptoms was com-
parable between both groups and significant differences
in HDRS scores were lacking. In patients receiving fo-
late supplementation, symptoms more often improved,
but the difference was only significant at the end of
treatment (week 6), in agreement with previous reports
[2, 34] , although the timing of response differed [18]
since the severity of depression did not differ between
both groups at the middle of the evaluation. Thus, in
this study, combination therapy with fluoxetine and fo-
lic did not accelerate the antidepressant response, but
augmented it. Possibly a longer treatment duration may
increase the beneficial effects of folate. In addition, in
contrast to other studies
[11, 12, 18] , folic acid concen-
tration in plasma was not decreased in our depressive
patients.
Folic acid supplementation may beneficially affect
chronic inflammatory diseases probably via a reduction
in homocysteine levels; in addition, it has been associated
with the prevention of non-fatal strokes, preservation of
cognitive function, immune function and psychiatric
disorders, e.g. depression
[23, 35] . This vitamin is re-
quired for pterin biosynthesis, and in depressed patients
there is a positive correlation between pterins and folate
[5] ; therefore, depressed patients might need folic acid
supplementation.
In our study, homocysteine levels were inversely pro-
portional to the levels of folate, which may be explained
by the need of methyl groups (e.g. from folate) for me-
thionine synthesis and homocysteine methylation. How-
ever, an association between homocysteine levels and
clinical changes was not found, which is in contrast to a
previous study indicating that high levels of homocyste-
ine may be neurotoxic and induce symptoms associated
with decreased biogenic amine synthesis
[20] , and, con-
sequently, decreased homocysteine levels may improve
symptoms and prevent the risk of cardiovascular disease,
which is frequently present in depressed patients
[36
39]
.
Interestingly, in a multiple regression analysis of an-
ger attacks adjusted for symptoms of depression, creati-
nine, vitamin B
12
, folate, age, smoking and alcohol, se-
rum levels of homocysteine were positively correlated
with the duration of the depressive episode
[40] . Defi-
ciencies in folate, vitamin B
12
, iron, zinc and selenium
we re more fr eque ntly rep or te d in d epr es sed p atie nts
[41] .
In addition, previous studies reported associations be-
tween low serum folate, but not vitamin B
12
and homo-
cysteine levels, and delayed onset of response to fluox-
etine in major depression [18] , the risk of relapse and re-
sistance to antidepressive treatment
[38, 39] . Serum and
red blood cell folate as well as plasma vitamin B
12
levels
were decreased and plasma homocysteine levels were in-
creased in depression
[42] . Moreover, white matter hy-
persensitivity in the brain was related to high homocys-
teine levels and negatively associated with folate
[43] . It
is interesting to note that vitamin B
6
, a cofactor of amino
acid transamination and decarboxylation, was also in-
volved in depression, since low plasma levels of vitamin
B
6
were associated with depression score, which encour-
age examining the role of the B complex in depression
and probably in other psychiatric disorders, too. Al-
though the therapeutic dose of folate may vary consider-
ably
[17, 23 ] , high doses may mask vitamin B
12
deficiency,
an effect not observed in the present work using pharma-
cological supplementation of folic acid. Although fur-
ther studies on the beneficial effects of folate are re-
quired, it has been suggested that 2 mg per day should be
given in major depression
[11] . This relatively elevated
dose of folate for patients with major depression may be
explained on the one hand by their lower dietary folate
intake according to their social class, and on the other
hand the raised need for folate due to depression. The
cap ac it y of h um an s f or p re se rv ing fola te is hi gh , a nd nor-
mal plasma values may be maintained even with cell de-
ficiency.
Fluoxetine administration resulted in decreased 5-HT
levels in lymphocytes after 6 weeks, despite the synaptic
increase in 5-HT availability by transporter blockade; the
observed results could be the consequence of its increased
catabolism to 5-HIAA and the corresponding excretion.
Increased levels of 5-HT in the culture medium of lym-
phocytes from depressed patients resulted in increased
proliferation
[44, 45] . However, only in lymphocytes of
patients receiving folic acid, a reduction in 5-HIAA was
noted, probably indicating the protection of 5-HT from
metabolism. Recent biochemical observations indicate a
modification of lymphocyte serotonergic system by folic
acid at the level of turnover rate, but obviously further
research is needed to document functional effects, since
these parameters have not been studied in immune cells
of depressed patients.
Thus, the reduction in 5-HT turnover may affect lym-
phocyte function via autocrine effects on 5-HT receptors.
Previously, increased lymphocyte proliferation probably
due to 5-HT
1A
receptor activation [44] , in addition to a
decreased 5-HT turnover rate and a decreased number of
5-HT transporters, were reported
[46] , possibly affecting
the immune response mediated by these cells. If folate
Effect of Folic Acid Supplementation on
Major Depression
Neuroimmunomodulation 2008;15:145–152
151
administration reduces homocysteine levels and also
modifies the effect of 5-HT on the immune system, co-
administration of folate in antidepressant treatment may
be of increasing interest.
A c k n o w l e d g m e n t s
This work was supported by the Fondo de Ciencia Tecnología
e Innovación (FONACIT) G-1387, Venezuela. We appreciate the
secretarial assistance of Mrs. Carolina Flores.
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... Прием фолатов с пищей строго ассоциирован с уровнем гомоцистеина крови, а при наличии гипергомоцистеинемии дополнительный прием фолатов корригирует это состояние, что подтверждено рядом исследований [6]. В исследованиях пациентов с сердечно-сосудистой патологией и высоким уровнем гомоцистеина было показано, что лечение фолиевой кислотой достоверно снижало уровень гомоцистеина, в то время как назначение В6 и В12 не оказывало аналогичного эффекта [7]. Кроме того, у пациентов с сердечно-сосудистыми заболеваниями и низким уровнем фолатов увеличивается риск формирования депрессии [8]. ...
... Синтетическая фолиевая кислота гораздо более широко изучена в акушерских исследованиях, а ее химическая стабильность позволяет использовать именно эту форму фолатов в качестве фортификации пищи в нескольких странах (США, Канада, Бразилия, Австралия). В связи с этим по данной форме накоплено огромное количество наблюдательных сведений [5][6][7]. Было отмечено, что фортификация пищи фолатами приводит к снижению частоты симптомов депрессии в популяции, причем у мужчин это опосредовано повышением уровня фолатов плазмы, а у женщин повышение данного уровня не отмечается [5]. ...
... В другом исследовании с таким же дизайном (n = 27), где доза фолиевой кислоты составляла 10 мг/сут в группе пациентов, получавших фолаты с флуоксетином (20 мг), после 6 нед лечения средняя оценка по шкале депрессии Гамильтона (HDRS) была значимо ниже, чем в группе плацебо с флуоксетином [7]. L-метилфолат также продемонстрировал положительный эффект в качестве адъювантной терапии в дополнение к традиционным антидепрессантам [6]. ...
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Currently, a growing amount of data is emerging on the role of various environmental factors (nutrients, gut microbiota, etc.) on formation of depression. The impact on these factors can be effective not only in treatment of major depressive disorder, but also in its early prevention. Therefore, a more detailed study of environmental factors in depression can lead both to a better understanding of the etiology and pathogenesis of the disorder and to optimization of approaches to its treatment. The aim of the review was to assess the potential role of a number of environmental factors associated with nutritional aspects and characteristics of individual microflora, as well as to review the prospects of a strategy for affecting these factors in treatment and prevention of depression.
... The folic acid pathway is illustrated in Figure 1 below. Numerous studies have demonstrated the association between depression and folate deficiency [98,99,[108][109][110][111]. L-methylfolate, the active form of vitamin B9, is the only form that can cross the blood-brain barrier [112]. ...
... Studies have shown the effectiveness of both folic acid and L-methylfolate as both a monotherapy and as an adjunctive therapy, suggesting the importance of assessing folate status in patients that appear to be "treatment resistant" [99,108,110,111]. In fact, Lmethylfolate is among the only medical foods licensed by the FDA for the treatment of depression [113,114]. ...
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Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.
... Clinical outcome at 6 weeks was assessed using HAM-D score. The HAM-D score was significantly lower in the intervention group, plasma homocysteine statistically significant decreased significantly after folic acid (p = 0.02) oral supplement was used, but no significant changes were observed in vitamin B 12 in the 6 weeks period [75]. Another RCT with 42 female outpatients with moderate to severe depression showed that augmentation of fluoxetine 20 mg daily with folic acid 5 mg daily was more beneficial than fluoxetine 20 mg daily and folic acid 1.5 mg supplement daily. ...
Article
Abstract Objectives To examine the strengths and limitations of existing data to provide guidance for the use of folate supplements as treatment, with or without other psychotropic medications, in various psychiatric disorders. To identify area for further research in terms of the biosynthesis of mechanism of folate and genetic variants in metabolic pathway in human. Methods A systematic review of published literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess whether folate supplements are beneficial in certain psychiatric disorders (depression, bipolar disorder, schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder). Methodology of this review is registered with Prospero (Registration number CRD 42021266605). Data sources Eligible studies were identified using a systematic search of four electronic databases: Embase, Pubmed, PsycINFO, and Cochrane. The search strategy covered the time period from 1974 to August 16th, 2021. Therefore, this review examines randomized control trials or open-label trials completed during this period. Results We identified 23 studies of folate supplements in various psychiatric disorders for critical review. Of these, 9 studies investigated the efficacy of folate supplements in major depressive disorders, 5 studies in schizophrenia, 6 studies in autism spectrum disorder, 2 studies in bipolar affective disorder and 1 study in attention deficit hyperactive disorder. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated. Limitation Our results are not representative of all types of studies such as case reports or case series studies, nor are they representative of the studies conducted in languages that are not in English or not translated in English. Conclusion Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.
... Clinical outcome at 6 weeks was assessed using HAM-D score. The HAM-D score was significantly lower in the intervention group, plasma homocysteine statistically significant decreased significantly after folic acid (p = 0.02) oral supplement was used, but no significant changes were observed in vitamin B 12 in the 6 weeks period [75]. Another RCT with 42 female outpatients with moderate to severe depression showed that augmentation of fluoxetine 20 mg daily with folic acid 5 mg daily was more beneficial than fluoxetine 20 mg daily and folic acid 1.5 mg supplement daily. ...
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Full-text available
Objectives To examine the strengths and limitations of existing data to provide guidance for the use of folate supplements as treatment, with or without other psychotropic medications, in various psychiatric disorders. To identify area for further research in terms of the biosynthesis of mechanism of folate and genetic variants in metabolic pathway in human. Methods A systematic review of published literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess whether folate supplements are beneficial in certain psychiatric disorders (depression, bipolar disorder, schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder). Methodology of this review is registered with Prospero (Registration number CRD 42021266605). Data sources Eligible studies were identified using a systematic search of four electronic databases: Embase, Pubmed, PsycINFO, and Cochrane. The search strategy covered the time period from 1974 to August 16th, 2021. Therefore, this review examines randomized control trials or open-label trials completed during this period. Results We identified 23 studies of folate supplements in various psychiatric disorders for critical review. Of these, 9 studies investigated the efficacy of folate supplements in major depressive disorders, 5 studies in schizophrenia, 6 studies in autism spectrum disorder, 2 studies in bipolar affective disorder and 1 study in attention deficit hyperactive disorder. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated. Limitation Our results are not representative of all types of studies such as case reports or case series studies, nor are they representative of the studies conducted in languages that are not in English or not translated in English. Conclusion Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.
... Long-term supplementation with folate and Vitamin B12 did not prevent the development of depression in healthy women (Okereke et al., 2015). Studies in patients with depression showed that folate and/or Vitamin B-12 including as an augmentation to antidepressants resulted in improved symptoms of depression in some studies (Coppen and Bailey, 2000;Kwok et al., 2019;Mech and Farah, 2016;Papakostas et al., 2012;Resler et al., 2008) but not others (Almeida et al., 2014;Bedson et al., 2014;Schefft et al., 2017). Greater reductions in depresssion were seen in depressed patients with the MHTFR polymorphism (Mech and Farah, 2016;Papakostas et al., 2014). ...
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Background : Homocysteine is an amino acid formed during metabolism of the essential amino acid methionine that plays an important role in energy metabolism and neurotransmitter synthesis. High levels of homocysteine have been linked to both depression and cardiovascular disease, however studies of depression have not always been consistent, possibly related to differences in methodology among studies. The study of twins in clinical research can be useful in controlling for confounding factors. The purpose of this study was to assess the relationship between depression and plasma homocysteine in a study of twins. Methods : Homocysteine concentration was assessed in twins (N=202) from the Vietnam Era Twin Registry, including twin pairs discordant for the diagnosis of Major Depressive Disorder (MDD) and twin pairs without MDD. Self reported depressive symptom levels were also measured as a continous variable using the Beck Depression Inventory (BDI). Results : The average homocysteine concentration was 7.9 µmol/L (2.1 µmol/L SD, range of 2.0 to 17.1 µmol/L). There were no within twin pair differences in homocysteine concentration within twin pairs discordant for MDD and within twin pairs that differed for BDI score. There was a significant pair-level relationship between depressive symptoms as measured by mean BDI score and homocysteine concentration, such that the higher the mean BDI score of the twin pair, the higher the mean homocystein of the pair (p<.001). Every 10 point increase in BDI score was associated with an 0.8 µmol/L increase in homocysteine concentration at the pair level. Conclusions : These findings are not consistent with a causal role for elevated homocysteine in the development of depression, but rather point to familial confounding or other factors that are shared by twin brothers and that contribute to both depression and homocysteine levels.
... Long-term supplementation with folate and vitamin B12 did not prevent the development of depression in healthy women [165]. Studies in patients with depression showed that folate and/or Vitamin B12, including as an augmentation to antidepressants, resulted in improved symptoms of depression in some studies [166][167][168][169][170] but not others [164,171,172]. Greater reductions in depression were seen in depressed patients with the MHTFR polymorphism [167,173]. ...
Article
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Introduction: There has long been an interest in the effects of diet on mental health, and the interaction of the two with stress; however, the nature of these relationships is not well understood. Although associations between diet, obesity and the related metabolic syndrome (MetS), stress, and mental disorders exist, causal pathways have not been established. Methods: We reviewed the literature on the relationship between diet, stress, obesity and psychiatric disorders related to stress. Results: Diet and obesity can affect mood through direct effects, or stress-related mental disorders could lead to changes in diet habits that affect weight. Alternatively, common factors such as stress or predisposition could lead to both obesity and stress-related mental disorders, such as depression and posttraumatic stress disorder (PTSD). Specific aspects of diet can lead to acute changes in mood as well as stimulate inflammation, which has led to efforts to assess polyunsaturated fats (PUFA) as a treatment for depression. Bidirectional relationships between these different factors are also likely. Finally, there has been increased attention recently on the relationship between the gut and the brain, with the realization that the gut microbiome has an influence on brain function and probably also mood and behavior, introducing another way diet can influence mental health and disorders. Brain areas and neurotransmitters and neuropeptides that are involved in both mood and appetite likely play a role in mediating this relationship. Conclusions: Understanding the relationship between diet, stress and mood and behavior could have important implications for the treatment of both stress-related mental disorders and obesity.
... Also, it was determined that the patients with lower level of folate had weaker response to antidepressants [47,48]. Several studies indicated improvement of depression symptoms after adding folic acid to antidepressants [49][50][51][52]. Previous studies reported that high intake of vitamin B12, selenium, and magnesium was associated with lower depression syndromes in pregnant and non-pregnant women [30,[53][54][55][56][57]. ...
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Background: The aim of the present study was to assess pregnant mothers' nutritional supply in each trimester and psychological status in postpartum with an emphasis on post pregnancy depression disorder and hypochondriasis. Methods: This was a three-year prospective cohort study that 1319 pregnant women referred to rural health centers in Bandar Abbas, Iran were enrolled. The data were collected using a checklist including socioeconomic and fertility characterize, food frequency questionnaire (FFQ) for measurement of dietary intake, Edinburgh Postnatal Depression Scale (EPDS) to diagnose postpartum depression (PPD), Evans hypochondriasis questionnaire was used to diagnose hypochondriasis. Results: The finding showed that prevalence of PPD and hypochondriasis were 91(6.8%) and 553(42%), respectively. The results showed that intake of iron, selenium, iodine, folate, vitamin C, B12, EPA in all trimesters and intake of vitamin c in second trimester was significantly associated with PPD (P<0.05); as intake of those micronutrients was significantly lower in women with PPD rather than women without that. Moreover, our finding showed that intake of iron, iodine, folate, selenium, EPA in all trimesters was significantly associated with hypochondriasis (P<0.05); as intake of those micronutrients was significantly lower in women with hypochondriasis rather than women without that. Conclusions: Considering the pregnancy and lactation are major nutritional stressors to body and our finding in relation between poor nutrition intake of iron, iodine, folate, selenium, EPA, vitamin C and mood disorders (PPD and hypochondriasis), greeter attention to nutritional factors in psychological status during postpartum is warranted.
Article
Background: Variability in individual drug response may delay time to relief of symptoms for various disease states. As pharmacogenomic (PGx) testing becomes more widespread, providers are tasked with determining when and in who PGx testing is most appropriate. The use of PGx testing in patients with depressive symptoms has shown some utility, but how this translates to a general population within a primary care setting has yet to be determined. Objective: The objective of this pilot study was to determine the effect of PGx testing on treatment decisions in patients with depressive symptoms in an interprofessional primary care setting. Methods: This was a retrospective observational study in which patients who underwent PGx testing for psychotropic medications between April 2019 and March 2021 at a private interprofessional primary care clinic were identified. Charts were reviewed to determine whether a resultant change was made to the prescribed psychotropic medication regimen based on PGx testing results. The number of antidepressants trialed before and after testing was also reviewed. Data were analyzed using descriptive statistics and t test where appropriate. Results: A total of 78 patients were included in the study. A total of 42 patients (53.8%) experienced a change to their antidepressant regimen after PGx testing. The most frequent change identified was the addition of another antidepressant (50%). This was followed by switching the antidepressant and then by an increase in dose of the prescribed antidepressant. No difference between the number of antidepressants trialed before and after testing was identified. Conclusion: PGx testing in an interprofessional primary care setting leads to a medication change in most patients in this study. Based on the changes identified, testing may be most useful in those beginning treatment with an antidepressant or in those who experience an inadequate response to their prescribed regimen.
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Objective Evaluate depression scores, response, and remission rates in patients with major depression receiving adjunct therapy with folate (L-Methylfolate or folic acid) compared to selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor (SSRI or SNRI) monotherapy. Methods Academic Search Premier, CINAHL Complete, Cochrane Database of Systematic Reviews, Medline with Full Text, PsychInfo, PubMed, ClinicalTrials.org, and Google Scholar were searched utilizing specific key words. Identified studies were independently screened for inclusion by two reviewers, were assessed for risk of bias using the Revised Cochrane risk-of-bias tool (RoB2), then meta-analyzed using a random effects model with Review Manager (5.4) software. Results The initial search revealed 293 articles with 6 randomized control trials ultimately meeting inclusion criteria. In patients with depression, analysis of 5 studies revealed a significantly lower Hamilton Depression Rating Scale (HAM-D) score in individuals treated with adjunct therapy with L-Methylfolate/folic acid [Mean Difference (MD): -2.16 (95% CI -3.62 to -0.69), p = 0.004], as well a combined HAM-D and Beck Depression Inventory-II (BDI-II) scores [standardized mean difference (SMD): -0.61 (95% Confidence Interval {CI} -0.97 to -0.24), p = 0.002]. This adjunct therapy also yielded an improved response rate [Risk Ratio (RR): 1.36 (95% CI: 1.16 to 1.59) P = 0.0001], increase in remission rate [RR: 1.39 (95% CI: 1.00 to 1.92) P = 0.05], and reduction in depression scores after varying durations of treatment, 4 week: [SMD = -0.38 (95% CI: –0.55 to -0.22) P ≤ 0.00001]; 6 week: [SMD = –0.94 (95% CI: –1.85 to -0.03) P = 0.04]; ≥ 8 week: [SMD= -0.57 (95% CI: -0.91 to -0.23) P = 0.0009]. Conclusion Adjunct therapy with L-Methylfolate or folic acid improves depression scale scores, patient response, and remission rates.
Chapter
Complementary and alternative medicine (CAM) encompasses a wide range of different non-mainstream therapies that have been increasingly used for treatment or adjunctive treatment of various ailments with mood disorders and “depressive difficulties” being two of the commonly CAM (self-)medicated conditions. We focus specifically on clinically diagnosed (in line with the standard criteria) depressive disorders, primarily major depressive disorder (MDD), and overview evidence of efficacy/safety of a range of CAM modalities addressing exclusively randomized controlled trials (RCTs) and systematic reviews/meta-analyses of RCTs. The list of addressed CAM interventions is not exhaustive: due to space limitation, addressed are interventions with at least a few conducted RCTs in the specific clinical conditions. We try to provide numerical and meaningful data as much as it is possible and to (a) indicate situations in which the reported data/estimates might have been “too enthusiastic” and (b) warn about heterogeneity of results that, together with other possible limitations (various biases and imprecision), results in uncertainty about the effects.
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Since the discovery of the folic acid in the 40´s, several studies have reported a linkage between its deficiency and psychiatric illness. The clinic relevance of folic acid deficiency deserves further research and has been inferred from clinical observations and better understanding of folate rol in brain metabolic pathways. This article reviews medical literature about the relation-ship between acid folic function and mental disorders, with emphasis on major depressive disorders
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The functioning of the brain is affected by the molecular concentrations of many substances that are normally present in the brain. The optimum concentrations of these substances for a person may differ greatly from the concentrations provided by his normal diet and genetic machinery. Biochemical and genetic arguments support the idea that orthomolecular therapy, the provision for the individual person of the optimum concentrations of important normal constituents of the brain, may be the preferred treatment for many mentally ill patients. Mental symptoms of avitaminosis sometimes are observed long before any physical symptoms appear. It is likely that the brain is more sensitive to changes in concentration of vital substances than are other organs and tissues. Moreover, there is the possibility that for some persons the cerebrospinal concentration of a vital substance may be grossly low at the same time that the concentration in the blood and lymph is essentially normal. A physiological abnormality such as decreased permeability of the blood-brain barrier for the vital substance or increased rate of metabolism of the substance in the brain may lead to a cerebral deficiency and to a mental disease. Diseases of this sort may be called localized cerebral deficiency diseases. It is suggested that the genes responsible for abnormalities (deficiencies) in the concentration of vital substances in the brain may be responsible for increased penetrance of the postulated gene for schizophrenia, and that the so-called gene for schizophrenia may itself be a gene that leads to a localized cerebral deficiency in one or more vital substances.
Article
Patients with methylenetetrahydrofolate reductase (MTHFR) deficiency often show psychiatric manifestations. Since a common variant of the MTHFR gene, T677(Ala), responsible for the thermolabile MTHFR with less than 50% specific MTHFR activity, has been reported, we examined whether the T677 allele is associated with psychiatric disorders in an unrelated Japanese population consisting of 297 schizophrenics, 32 patients with major depression, 40 patients with bipolar disorder, and 419 controls. The genotype homozygous for the T677 allele was significantly frequently observed in schizophrenics with an odds ratio of 1.9 (P = 0.0006), and in patients with major depression with an odds ratio of 2.8 (P = 0.005). Our data suggest associations of the MTHFR gene variant with schizophrenia and depression in the Japanese. Am. J. Med. Genet. 74:526–528, 1997. © 1997 Wiley-Liss, Inc.
Article
Several well-known observer scales, including the Hamilton Depression Scale (HAM-D), Montgomery-Asberg Scale (MADRS), Major Depression Rating Scale (MDS), Melancholia Scale (MES), and Inventory for Depressive Symptomatology (IDS) used for measuring severity of depressive states have been compared by their responsiveness in an open trial including patients treated with a combination of citalopram and mianserin. The patients fulfilled the Diagnostic and Statistical Manual (DSM)-IV criteria for major depressive episode, and all scored 18 or more on the HAM-D before treatment. Onset of antidepressant action was defined as an improvement of rating scale scores of 25% or more of pre-treatment scores. A response to treatment was defined as a reduction of 50% or more on the pre-treatment scores. The results showed that the number of treatment days until improvement was 11 to 13 with no difference between the scales. The days until response were between 18 and 21 with no difference between the scales. In conclusion, the depression scales were found to be equal in their ability to detect changes in depressive symptoms during treatment. The mean of days to response was 19 for the combination of citalopram and mianserin. This is similar to the response for the combination of fluoxetine and pinolol.
Article
Oral folic acid (pteroylglutamic acid) is generally regarded as not toxic for normal humans but it may cause neurological injury when given to patients with undiagnosed pernicious anemia. The vitamin should be given with caution to drug-treated epileptic patients because seizure control may be affected. Some studies suggest that folic acid supplements interfere with intestinal zinc absorption in humans and animals but others do not confirm such an effect. The weight of current evidence favors the view that daily supplements of 5-15 mg folic acid do not have significant adverse effects on Zn nutriture in healthy nonpregnant subjects. Because antifolate medications are now being used to treat a wide range of malignant and nonmalignant disorders, further investigation is needed concerning folate metabolism and the safety of supplements in patients with these disorders.
Article
The functioning of the brain is affected by the molecular concentrations of many substances that are normally present in the brain. The optimum concentrations of these substances for a person may differ greatly from the concentrations provided by his normal diet and genetic machinery. Biochemical and genetic arguments support the idea that orthomolecular therapy, the provision for the individual person of the optimum concentrations of important normal constituents of the brain, may be the preferred treatment for many mentally ill patients. Mental symptoms of avitaminosis sometimes are observed long before any physical symptoms appear. It is likely that the brain is more sensitive to changes in concentration of vital substances than are other organs and tissues. Moreover, there is the possibility that for some persons the cerebrospinal concentration of a vital substance may be grossly low at the same time that the concentration in the blood and lymph is essentially normal. A physiological abnormality such as decreased permeability of the blood-brain barrier for the vital substance or increased rate of metabolism of the substance in the brain may lead to a cerebral deficiency and to a mental disease. Diseases of this sort may be called localized cerebral deficiency diseases. It is suggested that the genes responsible for abnormalities (deficiencies) in the concentration of vital substances in the brain may be responsible for increased penetrance of the postulated gene for schizophrenia, and that the so-called gene for schizophrenia may itself be a gene that leads to a localized cerebral deficiency in one or more vital substances.
Article
To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-mumol/L tHcy increment is 1.6 (95% confidence interval [CI], 1.4 to 1.7) for men and 1.8 (95% CI, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-mumol/L tHcy increment) is 1.5 (95% CI, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 micrograms/d) reduces tHcy levels by approximately 4 mumol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13,500 to 50,000 CAD deaths annually could be avoided; fortification of food had the largest impact. A 5-mumol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements.
Article
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. 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. 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. 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.
Article
Plausible projections of future mortality and disability are a useful aid in decisions on priorities for health research, capital investment, and training. Rates and patterns of ill health are determined by factors such as socioeconomic development, educational attainment, technological developments, and their dispersion among populations, as well as exposure to hazards such as tobacco. As part of the Global Burden of Disease Study (GBD), we developed three scenarios of future mortality and disability for different age-sex groups, causes, and regions. We used the most important disease and injury trends since 1950 in nine cause-of-death clusters. Regression equations for mortality rates for each cluster by region were developed from gross domestic product per person (in international dollars), average number of years of education, time (in years, as a surrogate for technological change), and smoking intensity, which shows the cumulative effects based on data for 47 countries in 1950-90. Optimistic, pessimistic, and baseline projections of the independent variables were made. We related mortality from detailed causes to mortality from a cause cluster to project more detailed causes. Based on projected numbers of deaths by cause, years of life lived with disability (YLDs) were projected from different relation models of YLDs to years of life lost (YLLs). Population projections were prepared from World Bank projections of fertility and the projected mortality rates. Life expectancy at birth for women was projected to increase in all three scenarios; in established market economies to about 90 years by 2020. Far smaller gains in male life expectancy were projected than in females; in formerly socialist economies of Europe, male life expectancy may not increase at all. Worldwide mortality from communicable maternal, perinatal, and nutritional disorders was expected to decline in the baseline scenario from 17.2 million deaths in 1990 to 10.3 million in 2020. We projected that non-communicable disease mortality will increase from 28.1 million deaths in 1990 to 49.7 million in 2020. Deaths from injury may increase from 5.1 million to 8.4 million. Leading causes of disability-adjusted life years (DALYs) predicted by the baseline model were (in descending order): ischaemic heart disease, unipolar major depression, road-traffic accidents, cerebrovascular disease, chronic obstructive pulmonary disease, lower respiratory infections, tuberculosis, war injuries, diarrhoeal diseases, and HIV. Tobacco-attributable mortality is projected to increase from 3.0 million deaths in 1990 to 8.4 million deaths in 2020. Health trends in the next 25 years will be determined mainly by the ageing of the world's population, the decline in age-specific mortality rates from communicable, maternal, perinatal, and nutritional disorders, the spread of HIV, and the increase in tobacco-related mortality and disability. Projections, by their nature, are highly uncertain, but we found some robust results with implications for health policy.