Supplementation with B vitamins or n23 fatty acids and depressive
symptoms in cardiovascular disease survivors: ancillary findings from
the SUpplementation with FOLate, vitamins B-6 and B-12 and/or
OMega-3 fatty acids (SU.FOL.OM3) randomized trial1–4
Valentina A Andreeva, Pilar Galan, Marion Torre `s, Chantal Julia, Serge Hercberg, and Emmanuelle Kesse-Guyot
Background: Dietary factors might affect depressive symptoms.
Objective: In secondary data analyses, we examined effects of
supplementation with B vitamins or n23 (omega-3) fatty acids on
depressive symptoms in cardiovascular disease survivors.
Design: The SUpplementation with FOLate, vitamins B-6 and B-12
and/or OMega-3 fatty acids (SU.FOL.OM3) trial was a secondary
prevention trial (2003–2009; n = 2501) in which individuals aged
45–80 y were randomly assigned, by using a 2 · 2 factorial design,
to receive 0.56 mg 5-methyl-tetrahydrofolate and vitamins B-6
(3 mg) and B-12 (0.02 mg); EPA and DHA (600 mg) in a 2:1 ratio;
B vitamins and n23 fatty acids; or a placebo. Depressive symptoms
were evaluated at years 3 and 5 with the 30-item Geriatric Depres-
sion Scale (GDS). Overall and sex-specific ORs and 95% CIs were
estimated in 2000 participants by using factorial logistic regression.
Results: After a median of 4.7 y of supplementation, there was no
association between allocation to receive B vitamins and depressive
symptoms. However, the allocation to receive n23 fatty acids was
positively associated with depressive symptoms (GDS .10) in men
(adjusted OR: 1.28; 95% CI: 1.03, 1.61) but not in women.
Conclusions: We showed no beneficial effects of a long-term, low-dose
supplementation with B vitamins or n23 fatty acids on depressive symp-
toms in cardiovascular disease survivors. The adverse effects of n23
fatty acids in men merit confirmation. This trial was registered at
www.controlled-trials.com as ISRCTN41926726.
Am J Clin Nutr
Depressive symptoms adversely affect cardiovascular disease
(CVD)5prognosis and increase risk of cognitive decline (1, 2).
Pooled estimates suggested that one-third of all stroke survivors
experience depression, with a similar risk in early and late stages
of stroke recovery (3). In addition, all-cause mortality in acute
myocardial infarction patients has been predicted by mild de-
pressive symptoms that were not considered clinically signifi-
cant (4). Interest in nutritional status as a modifiable risk factor
for depression has been growing, and substantial clinical and
epidemiologic evidence has suggested a link between dietary
factors and mental health (5–7). The improvement of an in-
dividual’s dietary quality has been advanced as a means for the
reduction of depressive symptoms via an attainment of optimal
plasma folate concentrations (8). Indeed, folate deficiency has
been associated with decreased serotonergic function, decreased
effectiveness of antidepressants, and cognitive decline (5, 9).
The potential benefit of folate supplementation during the year
after a depressive episode has also been observed (10). A recent
randomized controlled trial (RCT) with stroke survivors showed
lower odds of depression after long-term daily supplementation
with folic acid (2 mg) and vitamins B-6 (25 mg) and B-12 (0.5
mg) (11). However, another RCT in hypertensive elderly men
showed nonsignificant effects of a similar treatment over 2 y
The impact of long-chain n23 (omega-3) PUFAs, especially
EPA and DHA, on mood disorders has also attracted consider-
able research interest (6, 13). Reviews and meta-analyses of
epidemiologic findings indicated a potentially beneficial effect
of these nutrients (as fish intake or n23 biomarker status) on
mood and depression (13, 14). Biologically, n23 PUFAs in-
fluence neuronal membrane stability, neurotransmitter bio-
synthesis, signal transduction, serotonin uptake, and monoamine
oxidase activity, and studies reported decreased amounts of both
EPA and DHA in depressed individuals (14). A review of RCT
1From the Nutritional Epidemiology Research Unit, University of Paris
13, Bobigny, France (VAA, PG, CJ, SH, and EK-G); the Victor Segalen
University, Bordeaux 2, Bordeaux, France (MT); and the Department of
Public Health, Avicenne Hospital, Bobigny, France (SH).
2None of the funding bodies had any involvement in the design and
conduct of the research, data analysis and interpretation, or writing and
approval of the manuscript.
3The SUpplementation with FOLate, vitamins B-6 and B-12 and/or
OMega-3 fatty acids trial was funded by the French National Research
Agency (grant R02010JJ), the Ministry of Health, Sodexo, Candia, Unilever,
Danone, Roche Laboratories, Merck Eprova AG, Pierre Fabre Laboratories,
and Catalent Pharma Solutions. VAA was supported in part by a nutrition
research grant from the Appert Institute/Uppia. Treatment capsules (active
and placebo) were provided free of charge by Roche Laboratories, Merck
Eprova AG, Pierre Fabre Laboratories, and Catalent Pharma Solutions. The
sponsors provided funding for operational aspects of the study.
4Address correspondence to VA Andreeva, Unite ´ de Recherche en E´pi-
de ´miologie Nutritonnelle, Universite ´ Paris 13, 74 rue Marcel Cachin, Bo-
bigny 93017, France. E-mail: firstname.lastname@example.org.
5Abbreviations used: CVD, cardiovascular disease; GDS, Geriatric De-
pression Scale; RCT, randomized controlled trial; SU.FOL.OM3, SUpple-
mentation with FOLate, vitamins B-6 and B-12 and/or OMega-3.
Received January 16, 2012. Accepted for publication April 12, 2012.
First published online May 30, 2012; doi: 10.3945/ajcn.112.035253.
Am J Clin Nutr 2012;96:208–14. Printed in USA. ? 2012 American Society for Nutrition
by guest on October 21, 2015
dietary B vitamin or n23 PUFA supplement use for the pre-
vention of depression in CVD survivors. The adverse impact of
n23 PUFAs observed in men necessitates confirmation before
broad conclusions can be drawn. With consideration of the serious
implications of mood disorders on the health and overall function-
ing of individuals, expanded multidisciplinary research is critical.
The authors’ responsibilities were as follows—PG and SH: designed and
conducted the research; VAA: led the writing of the manuscript and had pri-
mary responsibility for the final content; MTand VAA: performed data anal-
yses and a literature review; EK-G: provided methodological guidance; PG,
MT, CJ, SH, and EK-G: assisted with the interpretation of data and read and
edited each draft of the manuscript for important intellectual content; and all
authors: read and approved the final manuscript. Roche Laboratories, Merck
Eprova AG, Pierre Fabre Laboratories, and Catalent Pharma Solutions are
private pharmaceutical companies; Sodexo is a private event-management
company; Candia and Danone are private dairy-product companies; Unilever
is a private food and household–product company; and the Appert Institute/
Uppia is a private food-conservation company. None of the authors had any
competing interests and all authors were independent of the funding bodies.
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