Alcohol in ake, wine consump ion and he
de elopmen o dep ession: he PREDIMED s udy
Gea e al.
Gea e al. BMC Medicine 20132013, 11:192
h p://www.biomedcen al.com/1741-7015/x11/192
RESEARCH ARTICLE Open Access
Alcohol in ake, wine consump ion and he
de elopmen o dep ession: he PREDIMED s udy
Al edo Gea
1
, Juan J Beunza
2
, Ramón Es uch
3,4
, Almudena Sánchez-Villegas
3,5
, Jo di Salas-Sal adó
3,6
,
Pila Buil-Cosiales
7
, En ique Gómez-G acia
3,8
, Ma ía-Isabel Co as
3,9
, Dolo es Co ella
3,10
, Miquel Fiol
3,11
,
Fe nando A ós
3,12
, José Lape a
3,13
, Rosa-Ma ía Lamuela-Ra en ós
3,14
, Julia Wä nbe g
3,8
, Xa ie Pin ó
3,15
,
Lluis Se a-Majem
3,5
and Miguel A Ma ínez-González
1,3*
, o he PREDIMED GROUP
Abs ac
Backg ound: Alcoholic be e ages a e widely consumed. Dep ession, he mos p e alen men al diso de
wo ldwide, has been ela ed o alcohol in ake. We aimed o p ospec i ely assess he associa ion be ween alcohol
in ake and inciden dep ession using epea ed measu emen s o alcohol in ake.
Me hods: We ollowed-up 5,505 high- isk men and women (55 o 80 y) o he PREDIMED T ial o up o se en
yea s. Pa icipan s we e ini ially ee o dep ession o a his o y o dep ession, and did no ha e any his o y o
alcohol- ela ed p oblems. A 137-i em alida ed ood equency ques ionnai e adminis e ed by a die ician was
epea ed annually o assess alcohol in ake. Pa icipan s we e classi ied as inciden cases o dep ession when hey
epo ed a new clinical diagnosis o dep ession, and/o ini ia ed he use o an idep essan d ugs. Cox eg ession
analyses we e i ed o e 23,655 pe son-yea s.
Resul s: Mode a e alcohol in ake wi hin he ange o 5 o 15 g/day was signi ican ly associa ed wi h lowe isk o
inciden dep ession (haza d a io (HR) and 95% con idence in e al (95% CI) = 0.72 (0.53 o 0.98) e sus abs aine s).
Speci ically, wine consump ion in he ange o wo o se en d inks/week was signi ican ly associa ed wi h lowe
a es o dep ession (HR (95% CI) = 0.68 (0.47 o 0.98)).
Conclusions: Mode a e consump ion o wine may educe he incidence o dep ession, while hea y d inke s seem
o be a highe isk.
Keywo ds: Wine, Alcohol, Dep ession, Coho
Backg ound
Mos cul u es and coun ies include alcoholic be e ages
as pa o hei usual die . Alcohol in ake is di e en
o e wo ld egions ega ding he habi ual ype o be e age
and he pa e n o consump ion ( equency and a e age
in ake). In gene al e ms, he consump ion o alcoholic
be e ages is inc easing wo ldwide [1]. Unipola dep ession
is he mos p e alen men al diso de in he wo ld and i
is inc easing s eadily [2].
The simul aneous p esence o alcohol- ela ed p oblems
and dep ession is common [3]. Howe e , p oblema ic
in ake needs o be dis inguished om mode a e in ake.
P oblema ic alcohol in ake may be associa ed wi h dep es-
sion no only because o inc eased in ake o e hanol bu
also because o o he alcohol- ela ed unheal hy li es yles o
because o he social en i onmen su ounding p oblema ic
d inke s (job loss, amily p oblems, inancial p oblems o
o he addic ions). Any o hese ci cums ances may be a
po en ial igge o dep ession, e en in he absence o a
speci ic de imen al ole o e hanol.
Unipola dep ession and ca dio ascula disease a e likely
o sha e some common pa hophysiological mechanisms.
Mode a e alcohol in ake, especially alcohol om wine, has
been epea edly epo ed o be in e sely associa ed wi h
he incidence o ca dio ascula disease [4-6]. Some o he
esponsible mechanisms o his in e se associa ion a e
likely o be in ol ed also in a educed isk o dep ession
* Co espondence: [email p o ec ed]
1
Depa men o P e en i e Medicine and Public Heal h, Medical School-
Clinica Uni e sidad de Na a a, Pamplona, Spain
3
CIBER Fisiopa ología de la Obesidad y Nu ición (CIBERObn), Ins i u o de
Salud Ca los III, Mad id, Spain
Full lis o au ho in o ma ion is a ailable a he end o he a icle
© 2013 Gea e al.; licensee BioMed Cen al L d. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e
Commons A ibu ion License (h p://c ea i ecommons.o g/licenses/by/2.0), which pe mi s un es ic ed use, dis ibu ion, and
ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Gea e al. BMC Medicine 2013, 11:192
h p://www.biomedcen al.com/1741-7015/11/192
[7,8]. In he exis ing li e a u e abou non-p oblema ic
alcohol use and dep ession, longi udinal s udies a e incon-
sis en [9-20]. Howe e , none o hem has in es iga ed he
speci ic ole o each be e age. Nei he ha e hey used
epea ed measu emen s on alcohol in ake du ing ollow-up
o upda e he in o ma ion on exposu e o alcohol.
We p ospec i ely e alua ed he incidence o dep ession
among ligh o mode a e d inke s om an olde Medi e -
anean coho a high ca dio ascula isk using epea ed
measu emen s o in ake. An in e es ing cha ac e is ic
o his popula ion is ha wine was he mos equen ly
consumed alcoholic be e age. We also e alua ed speci ic-
ally he associa ion o wine wi h inciden dep ession, using
epea ed measu emen s o wine consump ion.
Me hods
Subjec s
We assessed pa icipan s om he PREDIMED S udy
(“P e ención con Die a Medi e ánea”(P e en ion wi h
Medi e anean Die )), which is a la ge, pa allel-g oup,
andomized, mul icen e , con olled, clinical ial conduc ed
in Spain. The aim o he PREDIMED ial was o assess
he e ec o he Medi e anean die on he p ima y
p e en ion o ca dio ascula disease (www.p edimed.es;
www.p edimed.o g) [21].
Pa icipan s we e men and women aged 55 o 80 and 60
o 80 yea s, espec i ely. They we e ee o ca dio ascula
diseasea baselineandme a leas oneo he wo ollowing
c i e ia: ype 2 diabe es melli us o he p esence o h ee
o mo e co ona y hea disease isk ac o s.
P e ious his o y o ca dio ascula disease, any se e e
ch onic illness, his o y o ood alle gy, in ole ance o
oli e oil o nu s, d ug addic ion o ch onic alcoholism
we e exclusion c i e ia in he PREDIMED ial. Subjec s
we e sc eened o p oblema ic use o alcohol using he
CAGE ques ionnai e (a ou -i em sc eening ool) [21] and
hey we e no included in he ial i hey answe ed
posi i ely o a leas wo ques ions on his ques ionnai e.
Pa icipan s who me he p e ious inclusion c i e ia
(n = 7,447) we e andomly assigned o h ee in e en ions:
Medi e anean die supplemen ed wi h ex a i gin oli e
oil, Medi e anean die supplemen ed wi h mixed nu s o
a con ol g oup. They we e annually in e iewed by a
die ician, ob aining in o ma ion abou li es yle, die and
inciden diseases. Fu he aspec s o he me hods and
design o he PREDIMED ial ha e been epo ed else-
whe e in de ail [22,23]. The Resea ch and E hic Commi ee
o he Hospi al Clínic (Ba celona, Spain), acc edi ed by he
Depa men o Heal h and Human Se ices and egula ed
by he Fede alwide Assu ance o he P o ec ion o Human
Subjec s o In e na ional (Non-US) Ins i u ions # 00000738
app o ed he s udy p o ocol on 16 July 2002. This ial has
been egis e ed in he London Cu en Con olled T ials
wi h he numbe ISRCTN 35739639 [24]. All pa icipan s
p o ided w i en in o med consen .
Ou o 7,447 pa icipan s, we excluded 153 pa icipan s
wi h o al ene gy in ake ou o p ede ined limi s (800 and
4,000 Kcal/day o men and 500 and 3,500 Kcal/day
o women) [25]. Ano he 1,579 subjec s who epo ed a
baseline p e alen dep ession, p e ious his o y o dep ession
o use o an idep essan d ugs we e also excluded ( o
ensu e he empo al sequence and, he e o e, a oid e e se
causa ion bias). Addi ionally, 210 pa icipan s we e los o
ollow-up o did no ha e alcohol in o ma ion and
we e also excluded. Finally, a subsample o 5,505 pa -
icipan s was included in he analyses o he p esen s udy
(Addi ional ile 1).
Exposu e assessmen
Alcohol in ake was assessed a baseline wi h a alida ed
137-i em semi-quan i a i e ood- equency ques ionnai e
(FFQ), which included nine ques ions on consump ion
o di e en alcoholic be e ages (di e en ypes o wine,
bee and spi i s). In he alida ion s udy o he Spanish
e sion o his ques ionnai e, he in a-class co ela ion
coe icien be ween alcohol in ake om he FFQ and
epea ed ood eco ds was 0.82 [26]. This FFQ was
epea edly adminis e ed each yea du ing ollow-up.
In o de o upda e alcohol in o ma ion, we conside ed
alcohol in ake using epea ed measu emen s o die om
all a ailable FFQs. Pa icipan s we e di ided in o ou
g oups acco ding o hei alcohol in ake: abs aine s,
hose who epo ed d inking less han 5 g/day, hose wi h
an in ake anging om >5 o 15 g/day, and he ou h
g oup wi h an in ake highe han 15 g/day.
To assess he speci ic ole o wine, pa icipan s we e
di ided in o i e g oups acco ding o hei a e age numbe
o weekly d inks o wine: abs aine s, less han one d ink/
week, one o less han wo d inks/week, wo o se en
d inks/week, and mo e han se en d inks/week. Pa ici-
pan s who did no d ink wine bu d ank o he ypes o
alcoholic be e ages we e excluded om hese speci ic
analyses.
Ou come assessmen
An inciden case o dep ession was de ined as a diagnosis
o dep ession made by a physician and epo ed by pa ici-
pan s in any o he ollow-up in e iews, o a posi i e
epo o habi ual use o an idep essan d ugs.
Con ounde assessmen
We ob ained in o ma ion abou medical, socio-demo-
g aphic, an h opome ic and li es yle a iables wi h
s anda dized ques ionnai es (see www.p edimed.es) a
he baseline in e iew.
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S a is ical analysis
Cox eg ession models we e used o assess he ela ionship
be ween ca ego ies o baseline alcohol in ake and he
subsequen incidence o dep ession du ing ollow-up.
Haza d a ios (HR) and hei 95% con idence in e als
(95% CI) we e calcula ed using he abs aine s g oup as
he e e ence ca ego y. En y ime was de ined as he
da e a ec ui men . Exi ime was de ined as he da e a
diagnosis o dep ession o cases and, o pa icipan s who
did no de elop dep ession, as he da e when comple ing
he las in e iew, 1 Decembe 2010, o da e a dea h,
whiche e came i s . We adjus ed he mul i a iable models
o he ollowing po en ial con ounde s: age, sex, smoking
s a us (non-smoke s, ex-smoke s and cu en smoke s),
physical ac i i y (MET-min/d), o al ene gy in ake (Kcal/
day), baseline body mass index (kg/m
2
), ma i al s a us
(ma ied o no ), in e en ion g oup (Medi e anean die +
i gin oli e oil, Medi e anean die + nu s, low a die ),
ec ui ing cen e (14 cen e s), educa ional le el (in i e
ca ego ies om illi e a e o uni e si y g adua e), and
numbe o pe sons li ing a home (li ing alone o no ).
We e alua ed he in e ac ion be ween sex and alcohol
in ake on he de elopmen o dep ession by calcula ing
he likelihood a io es be ween he ully adjus ed model
and he same model adding he in e ac ion p oduc - e m.
To ake ad an age o he yea ly epea ed measu emen s o
die , we upda ed he calcula ion o alcohol in ake o
pa icipan s e e y yea om baseline o he incidence o
dep ession om he epea ed FFQs. To upda e alcohol
in ake wi h all a ailable longi udinal da a, and o analyze
he associa ion be ween alcohol in ake and dep ession
a all ime-poin s simul aneously, we used gene alized
es ima ing equa ions (GEE) wi h S a a 12.0 (S a aCo p,
CollegeS a ion,TX,USA).Weassumedabinomialdis-
ibu ion wi h logi models and he uns uc u ed ma ix
as he wo king co ela ion s uc u e [27]. We de ined
he coho isk as pa icipan s who emained ee o
dep ession a he beginning o each wo-yea ollow-up
pe iod. Pa icipan s who had been classi ied as inciden
cases we e excluded om subsequen ollow-up. Then,
only he i s inciden case o dep ession was conside ed
as ou come. In he analysis o epea ed measu emen s,
o allow o a su icien ly long ollow-up pe iod, we
modeled he incidence o dep ession in ela ion o he
cumula i e a e age alcohol in ake om all a ailable
die a y ques ionnai es up o he s a o each wo-yea
ollow-up in e al, bu we excluded cases occu ing in
he i s yea o ha pe iod and ook in o accoun only
new cases occu ing a e one yea . Fo example, o a
pa icipan ec ui ed in 2005 he incidence o dep ession
om 2007 h ough 2008 was ela ed o he alcohol in ake
epo ed on he 2005 and 2006 ques ionnai es. The e o e,
we assumed, an induc ion pe iod longe han one yea
bu no longe han wo yea s and alcohol in ake was
conside ed as he cumula i e a e age o all a ailable FFQs,
om baseline o he beginning o each wo-yea ollow-up
pe iod. Se e al sensi i i y analyses we e conduc ed e i -
ing Cox eg ession analyses a e a) es ablishing he 1
s
and he 99
h
o b) he 5
h
and 95
h
pe cen iles o ene gy
in ake as allowable limi s, c) a e excluding diabe ics, d)
a e excluding pa icipan s olde han 75 yea s, e) a e
excluding pa icipan s younge han 65 yea s, ) a e
depu a ing he abs aine s’g oup (excluding pa icipan s
who epo ed any alcohol in ake h oughou hei li e bu
no cu en ly a baseline), g) a e including pa icipan s
wi h a p io his o y o dep ession a baseline and including
his a iable in he mul iple adjus ed model, and h) a e
es ablishing a wo- o h ee-yea induc ion pe iod (ins ead
o one o wo yea s) be ween exposu e and ou come in
he epea ed measu emen analyses. Mo eo e , o assess
he in luence o wine consump ion on he de elopmen o
dep ession, we conduc ed bo h Cox eg ession and GEE
analyses, using abs aine s as he e e ence ca ego y. In hese
analyses, we adjus ed o he same po en ial con ounde s as
men ioned abo e, and also o alcohol in ake om o he
sou ces. Addi ionally, we e- an he analyses o wine
consump ion among only-wine d inke s o con ol o
con ounding by o he alcoholic be e ages.
Mo eo e , we e alua ed he po en ial non-linea associ-
a ion be ween alcohol in ake and inciden dep ession wi h
he use o es ic ed cubic splines, o pa icipan s d inking
no mo e han 80 g ams o alcohol pe day (99.42% o
pa icipan s) [28].
Finally, we examined he incidence and eco e y om
dep ession applying ixed-e ec s eg ession as sugges ed
by Fe gusson e al. [29] o con ol o obse ed and non-
obse ed ac o s ha do no a y o a subjec o e ime.
Resul s
The main cha ac e is ics o he 5,505 pa icipan s (2,683
males and 2,822 emales) acco ding o hei o al alcohol
in ake a e shown in Table 1. As men ioned be o e, his
Medi e anean popula ion consis ed o olde men and wo-
men, wi h a mean age o 67 yea s. Highe alcohol in ake
was posi i ely associa ed wi h being male (88% o pa ici-
pan s d inking mo e han 15 g/day we e male), p ac icing
mo e leisu e- ime physical ac i i y, being a cu en o o -
me smoke , ha ing highe o al ene gy in ake, being ma -
ied, bu i was in e sely associa ed wi h educa ional le el.
A o al o 443 inciden cases o dep ession we e iden i-
ied du ing he ollow-up pe iod, which acc ued 23,655
pe son-yea s.
The Cox eg ession analysis using baseline alcohol in ake
as exposu e showed an in e se associa ion be ween o al
alcohol in ake and he incidence o dep ession, wi h no sig-
ni ican linea o quad a ic end in he mul iple-adjus ed
analyses. In he mul iple-adjus ed model, only he associ-
a ion o he ca ego y o low- o-mode a e in ake (>5 o 15
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g/day) emained s a is ically signi ican (HR (95% CI) =
0.72 (0.53 o 0.98)) (Table 2). Examining he associa ion o
hose pa icipan s who d ank mo e han 40 g/day, we
ound ha hey we e a highe isk bu his associa ion was
no s a is ically signi ican , p obably due o he small num-
be o hea y d inke s (HR (95% CI = 1.34 (0.69 o 2.59)).
In he epea ed-measu emen analyses using as exposu e
he yea ly upda ed in o ma ion on alcohol in ake, we
obse ed a s onge in e se associa ion. We ound a
s a is ically signi ican in e se associa ion o ligh d inke s
(>0 o 5 g/day) wi h a ela i e isk (95% CI) o 0.73 (0.57 o
0.95) and also o low- o-mode a e d inke s (>5 o 15
g/day) wi h a ela i e isk o 0.69 (0.50 o 0.96). We
ound no e ec modi ica ion o alcohol in ake by sex
(P= 0.45). Al hough he in e ac ion was non-signi ican ,
we e- an he analyses sepa a ely o men and women o
ake in o accoun biological di e ences be ween he sexes.
The esul s a e a ailable in he supplemen a y ma e ial
(Addi ional ile 2).
To accoun o a non-linea associa ion, we used e-
s ic ed cubic spline analysis. The U-shaped associa ion
ound, ep esen ed in Figu e 1, showed a consis en p o-
ec ion agains inciden dep ession o baseline mode a e
alcohol in ake.
Table 1 Baseline cha ac e is ics o pa icipan s acco ding o baseline alcohol in ake
Alcohol in ake ca ego ies (g/day)
0 >0 o 5 >5 o 15 >15
N 1,818 1,356 1,279 1,052
Sex ( emale %) 78 59 38 12
Age (yea s) 68.5 (6.1) 67.0 (6.1) 66.4 (6.2) 65.6 (6.1)
BMI (kg/m
2
) 30.3 (4.1) 30.0 (3.9) 29.4 (3.5) 29.3 (3.3)
Leisu e ime physical ac i i y (MET-min/d) 201 (210) 230 (232) 267 (276) 318 (270)
Seconda y school o highe (%) 13 23 28 36
Cu en smoke s (%) 7 12 17 29
Fo me smoke s (%) 15 24 36 44
Ma i al s a us (% ma ied) 71 78 84 89
Li ing alone (%) 12 9 7 5
To al ene gy in ake (Kcal/day) 2,054 (511) 2,184 (509) 2,330 (511) 2,595 (533)
Alcohol (g/day) - 2.0 (1.4) 9.8 (2.7) 35 (17)
Wine (g alcohol/day) - 1.3 (1.4) 7.4 (3.7) 25 (16)
Bee (g alcohol/day) - 0.5 (0.9) 1.7 (2.7) 4.8 (8.4)
Spi i s (g alcohol/day) - 0.2 (0.5) 0.6 (1.5) 4.2 (8.8)
Mean and S anda d De ia ions, o %. The PREDIMED S udy 2003 o 2010. BMI, body mass index; MET, me abolic equi alen ask.
Table 2 Risks o dep ession acco ding o ca ego ies o daily alcohol in ake
Alcohol in ake ca ego ies (g/day) 0 >0 o 5 >5 o 15 >15 P o line end
Baseline alcohol in ake
a
Cases/Pe son-yea s 195/7,777 114/5,728 79/5,390 55/4,760
C ude model 1 (Re .) 0.79 (0.63 o 1.00) 0.59 (0.46 o 0.77) 0.44 (0.33 o 0.60) <0.001
Age and sex-adjus ed 1 (Re .) 0.91 (0.72 o 1.15) 0.81 (0.62 o 1.07) 0.81 (0.58 o 1.14) 0.347
Mul iple-adjus ed model
c
1 (Re .) 0.97 (0.75 o 1.25) 0.72 (0.53 o 0.98) 0.79 (0.53 o 1.16) 0.522
Upda ed alcohol in ake
b
C ude model 1 (Re .) 0.63 (0.49 o 0.81) 0.49 (0.37 o 0.66) 0.37 (0.26 o 0.52) <0.001
Age and sex-adjus ed 1 (Re .) 0.73 (0.56 o 0.94) 0.71 (0.52 o 0.97) 0.71 (0.48 o 1.05) 0.727
Mul iple-adjus ed model
c
1 (Re .) 0.73 (0.57 o 0.95) 0.69 (0.50 o 0.96) 0.69 (0.46 o 1.04) 0.773
a
Haza d a ios (95% con idence in e als) o inciden dep ession acco ding o ca ego ies o baseline daily alcohol in ake.
b
Rela i e isks (95% con idence in e als) o ca ego ies o upda ed alcohol in ake, using epea ed measu emen s o die du ing ollow-up. To a oid e e se
causali y bias, an induc ion pe iod o a leas one yea , bu no longe han wo yea s was assumed. We conside ed as inciden cases o dep ession hose occu ing
only du ing he second yea o e e y wo-yea ollow-up in e al.
c
Adjus ed o age, sex, smoking, physical ac i i y (MET-min/d), o al ene gy in ake (Kcal/day), baseline body mass index (kg/m
2
), ma i al s a us, in e en ion g oup,
ec ui ing cen e , educa ional le el and he numbe o pe sons li ing a home.
The PREDIMED S udy 2003 o 2010.
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D inking wine ( wo o se en d inks/week) was in e sely
associa ed wi h he incidence o dep ession (Table 3). In
he mul iple-adjus ed model, we ound a HR (95% CI) o
0.68 (0.47 o 0.98) o he baseline consump ion o wo o
se en d inks/week o wine. Using epea ed measu emen s
o upda e wine consump ion, we also obse ed a s eng h-
ening o his in e se associa ion wi h a ela i e isk o 0.57
(0.40 o 0.79) o hose who d ank wo o se en d inks/
week o wine. In ou sample, 1,350 pa icipan s we e only-
wine d inke s. Among hem he esul s we e consis en
wi h hose p e iously discussed (Table 3). Wine consump-
ion accoun ed o 82% o alcohol in ake a iabili y in his
sample. The numbe o only-bee d inke s was jus 308
and he numbe o only-spi i s d inke s was 61. Only
1.63% o pa icipan s d ank mo e han one d ink/day o
bee , and only 0.09% o spi i s. Consequen ly, we could
no do o bee o spi i s he ype o sepa a e analysis ha
we did o wine. In o de o in es iga e possible sou ces o
bias in he es ima ion o he ela ionship be ween alcohol
in ake and dep ession, we conduc ed se e al sensi i i y
analyses (Table 4). Resul s did no subs an ially change
excep when excluding diabe ics and o o he analyses
wi h a subs an ial numbe o exclusions, p obably due o a
lack o s a is ical powe .
Resul s we e also consis en when we in es iga ed he
incidence and eco e y om dep ession using ixed-e ec s
models (Addi ional ile 3).
Discussion
We ound ha o al low- o-mode a e alcohol d inking
(5 o 15 g/day) was associa ed wi h lowe isk o dep ession.
A s onge in e se associa ion was ound o low- o-mode -
a e wine-d inke s ( wo o se en glasses/week).
These esul s seem pa adoxical as p e ious s udies ound
a di ec associa ion be ween alcohol in highe amoun s,
especially Alcohol Use Diso de s (AUD), and dep essi e
symp oms, [11,17-20,30]. Howe e , lowe amoun s o alco-
hol in ake migh exe a p o ec ion as i has been obse ed
o co ona y hea disease (CHD). In ac , i is belie ed ha
dep ession and CHD sha e common pa hophysiological
mechanisms [30,31]. Only one p e ious coho , including
pa icipan s wi h a high educa ional le el, assessed low-
o-mode a e le els o in ake and ound a simila in e se
associa ion (HR (95% CI); 0.65 (0.49 o 0.86)) o he
same angeo exposu e5 o15g/day ha weha eob-
se ed [9]. The esul s o ou s udy and ha p e ious
coho a e, he e o e, closely consis en . The p ac ical
absence o hea y d inke s in ou sample and in ha co-
ho , oge he wi h he la ge p opo ion o pa icipan s
exposed o low- o-mode a e in akes a e likely explana-
ions o he di e ging esul s wi h espec o coho s
including hea y d inke s. The esul s o hose s udies
ha e o be ca e ully in e p e ed. In se e al p e ious
c oss-sec ional s udies, a s ong posi i e associa ion was
ound. The e o e, he de ini ion o a clea empo al se-
quence is necessa y o p eclude he possibili y o a e e se
causa ion bias [3]. Some longi udinal s udies ha e assessed
he e e se di ec ion o his associa ion, ha is, he conse-
quences o dep ession on alcohol in ake. They ha e ound
di ec associa ions; subjec s wi h dep ession end o in-
c ease hei alcohol in ake as a consequence o hei mood
diso de [2]. The e o e, in some c oss-sec ional analyses,
he posi i e associa ion ound is likely o be he esul o
he di ec e ec o dep ession on alcohol in ake, which may
o e come he possible in e se associa ion be ween low- o
-mode a e alcohol in ake and dep ession isk. They can
also cap u e he de imen al e ec s o highe amoun s o
alcohol in ake on dep ession isk. In con as , in a longi u-
dinal analysis, he empo al sequence is p ese ed, and e-
e se causa ion bias is less likely. In o de o minimize
he isk o ha bias, we assumed an induc ion pe iod o a
leas one yea and we conduc ed a sensi i i y analysis as-
suming an al e na i e induc ion pe iod o wo o h ee
yea s in he epea ed measu emen analyses. Ea ly cases
may be subclinical cases o dep ession a he beginning o
he in e al and may co espond o subjec s who changed
hei alcohol in ake be o e de eloping o e clinical dep es-
sion. The ac ha he esul s o hese sensi i i y analyses
a e consis en wi h he main esul s gi es u he suppo
o ou indings. Mo eo e , inciden cases o dep ession did
no change hei alcohol in ake di e en ly om hose who
we e no inciden cases (P>0.1; da a no shown).
The di e ences be ween ou esul s and hose o p e ious
s udies could also be explained by he di e en a e age
alcohol in ake be ween popula ions, he di e en pa e n
Figu e 1 Dose– esponse ela ionship be ween alcohol in ake
(g/day) and dep ession isk (HR and 95% CI). Res ic ed cubic
spline model. The PREDIMED S udy 2003 o 2010. The black line
ep esen s he HR and he dashed lines ep esen he 95%
con idence in e al. Adjus ed o age, smoking, physical ac i i y
(MET-min/d), o al ene gy in ake (Kcal/day), baseline body mass
index (kg/m
2
), ma i al s a us, in e en ion g oup, ec ui ing cen e ,
educa ional le el and he numbe o pe sons li ing a home.
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o consump ion and especially because he p edominan
ype o be e age consumed is di e en , wine being he
p e e en ial be e age in ou coho . The PREDIMED
ial includes an olde , adi ional Spanish Medi e anean
popula ion, ha consumed chie ly wine, and mainly in a
con ex o socializa ion wi h amily o iends. Subjec s
wi h p oblema ic use o alcohol (≥2 posi i e answe s in
he CAGE ques ionnai e) [21] we e explici ly excluded
om his ial because his was one o he exclusion c i e ia.
Mo eo e , hey we e in a ial whe e an in e en ion wi h
a Medi e anean die was done, including he ad ice o
consume wine mode a ely only o hose who we e
al eady wine d inke s a incep ion. Howe e , he in e en-
ion designed o his ial did no a ain any signi ican
Table 4 Sensi i i y analyses
To al cases/pe son-yea s >5 o 5 g/day
O e all 443/23,655 0.72 (0.53 o 0.98)
Ene gy limi s: pe cen iles 5 o 95 403/21,681 0.78 (0.57 o 1.06)
Ene gy limi s: pe cen iles 1 o 99 444/23,675 0.71 (0.53 o 0.96)
Excluding diabe ics 227/11,653 0.96 (0.64 o 1.44)
Excluding pa icipan s olde han 75 389/21,200 0.73 (0.56 o 1.25)
Excluding pa icipan s younge han 65 307/14,785 0.75 (0.52 o 1.06)
Depu a ing abs aine s’g oup
a
422/22,882 0.75 (0.55 o 1.02)
Including pa icipan s wi h p io dep ession a baseline 817/25,868 0.72 (0.57 o 0.90)
Upda ed alcohol in ake assuming induc ion pe iod: 1 o 2 yea s
b
- 0.69 (0.50 o 0.96)
Upda ed alcohol in ake assuming induc ion pe iod: 2 o 3 yea s
b
- 0.68 (0.47 o 1.00)
a
A e excluding hose pa icipan s who epo ed any alcohol in ake h oughou hei li e bu no cu en ly a baseline.
b
Repea ed-measu emen analysis. Rela i e isks (95% con idence in e al) o inciden dep ession acco ding o yea ly upda ed measu emen s o alcohol in ake.
Conside ing inciden cases du ing he las yea o e e y wo-yea ollow-up in e al.
The PREDIMED S udy 2003 o 2010.
All adjus ed o age, sex, smoking, physical ac i i y (MET-min/d), o al ene gy in ake (Kcal/day), baseline body mass index (kg/m
2
), ma i al s a us, in e en ion
g oup, ec ui ing cen e , educa ional le el, he numbe o pe sons li ing a home and alcohol in ake a baseline.
Table 3 Risks o dep ession acco ding o weekly wine consump ion
Wine: d inks/week Abs aine s <1 1 o <2 2 o 7 >7
Baseline wine consump ion
a
Cases/Pe son-yea s 195/7,777 44/2,461 28/1,708 57/3,183 32/6,828
Age and sex-adjus ed model 1 (Re .) 1.05 (0.78 o 1.42) 0.82 (0.55 o 1.22) 0.75 (0.54 o 1.05) 0.79 (0.60 o 1.04)
Mul iple-adjus ed model
c
1 (Re .) 1.00 (0.72 o 1.39) 0.93 (0.61 o 1.43) 0.70 (0.48 o 1.00) 0.78 (0.57 o 1.06)
Mul iple-adjus ed model
d
1 (Re .) 0.99 (0.71 o 1.37) 0.92 (0.60 o 1.41) 0.68 (0.47 o 0.98) 0.76 (0.56 o 1.04)
Upda ed wine consump ion
b
Age-adjus ed model 1 (Re .) 0.64 (0.46 o 0.89) 0.86 (0.58 o 1.27) 0.59 (0.43 o 0.82) 0.70 (0.48 o 1.02)
Mul iple-adjus ed model
c
1 (Re .) 0.64 (0.46 o 0.89) 0.87 (0.58 o 1.29) 0.57 (0.41 o 0.80) 0.68 (0.46 o 1.01)
Mul iple-adjus ed model
d
1 (Re .) 0.63 (0.46 o 0.89) 0.86 (0.58 o 1.28) 0.57 (0.40 o 0.79) 0.66 (0.45 o 0.99)
Baseline wine consump ion (Only wine-d inke s)
a
Cases/Pe son-yea s 195/7,777 40/1,454 13/752 25/1,363 26/2,236
Age-adjus ed model 1 (Re .) 1.13 (0.80 o 1.59) 0.79 (0.45 o 1.38) 0.86 (0.56 o 1.30) 0.59 (0.39 o 0.90)
Mul iple-adjus ed model
c
1 (Re .) 1.18 (0.81 o 1.72) 0.91 (0.49 o 1.69) 0.81 (0.50 o 1.30) 0.55 (0.35 o 0.87)
Upda ed wine consump ion (Only wine-d inke s)
b
Age-adjus ed model 1 (Re .) 0.54 (0.34 o 0.87) 0.93 (0.52 o 1.66) 0.58 (0.36 o 0.92) 0.52 (0.24 o 1.14)
Mul iple-adjus ed model
c
1 (Re .) 0.55 (0.34 o 0.87) 0.93 (0.52 o 1.66) 0.57 (0.36 o 0.92) 0.52 (0.23 o 1.18)
a
Haza d a ios (95% con idence in e als) o inciden dep ession acco ding o ca ego ies o baseline daily alcohol in ake.
b
Rela i e isks (95% con idence in e als) o ca ego ies o upda ed alcohol in ake, using epea ed measu emen s o die du ing ollow-up. To a oid e e se
causali y bias, an induc ion pe iod o a leas one yea , bu no longe han wo yea s was assumed. We conside ed as inciden cases o dep ession hose occu ing
only du ing he second yea o e e y wo-yea ollow-up in e al.
c
Adjus ed o age, smoking, physical ac i i y (MET-min/d), o al ene gy in ake (Kcal/day), baseline body mass index (kg/m
2
), ma i al s a us, in e en ion g oup,
ec ui ing cen e , educa ional le el and he numbe o pe sons li ing a home.
d
Adding alcohol om sou ces o he han wine o he p e ious mul iple-adjus ed model.
The PREDIMED S udy 2003 o 2010.
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change in a e age le els o alcohol in ake (−1.4 g/day, −1.4
g/day, and −0.9 g/day in he Medi e anean die + i gin
oli e oil, Medi e anean die + nu s and con ol g oups, e-
spec i ely) wi hou any be ween-g oup signi ican di e -
ence. In addi ion, he Medi e anean die has also been
associa ed wi h lowe incidence o dep ession [32]. The e-
o e, dummy a iables o he wo ac i e in e en ion
g oups we e included in he mul iple-adjus ed model as
po en ial con ounde s.
The ela ionship be ween alcohol in ake and dep ession
is biologically di e en among men and women [20,33,34].
Fo ins ance, alcohol bioa ailabili y is di e en be ween
sexes [35], and women seem o be mo e likely o de elop
dep ession [36]. The e o e, we p esen ed he analyses s a i-
ied by sex despi e he e being no e idence o s a is ical
in e ac ion by sex.
Besides he sensi i i y analysis men ioned abo e, we
conduc ed eigh o he sensi i i y analyses o explo e
u he po en ial sou ces o bias. The e e ence ca ego y
in he main analysis was he abs aine s’g oup. This g oup
may include o me d inke s. The e o e, we excluded om
he abs aine s’g oup all pa icipan s who epo ed d inking
alcohol e e in he /his pas li e, and he esul s emained
simila . Howe e , he esul s became non-signi ican a e
he exclusion o p e alen diabe ics a baseline. This ac
maybeexplainedbyalosso s a is icalpowe because
almos 50% o ou pa icipan s we e diabe ics. Al e na i ely,
i migh be a ibu ed o a be e disease classi ica ion
among diabe ic han among non-diabe ic pa icipan s.
Diabe ics usually a e mo e likely o ha e mo e equen
medical isi s due o hei diabe es; he e o e, hey ha e
mo e oppo uni ies o ecei e a medical diagnosis o
dep ession han non-diabe ic pa ien s.
To ou knowledge, wi h he excep ion o he ecen
esul s o he Uni e si y o Na a a ollow-up S udy
(“Seguimien o Uni e sidad de Na a a”(SUN coho )),
no o he la ge p ospec i e coho s udy has p e iously
epo ed conclusi e esul s abou he ela ionship be ween
speci ic alcoholic be e ages and inciden dep ession.
Non-alcoholic componen s o wine can accoun o he
in e se associa ion ound in ou s udy. Fo ins ance,
ans- es e a ol has been pos ula ed as a neu op o ec i e
subs ance [37-40]. P e ious in es iga ions sugges ha he
hippocampal complex may play a ole in he de elopmen
o majo dep ession [41]. This neu op o ec ion applied o
he hippocampus may p e en mode a e wine d inke s
om de eloping dep ession.
An al e na i e po en ial explana ion o his associa ion
can be ha wine-d inke s o mode a e d inke s migh be
heal hie in o he aspec s han non-wine d inke s o
non-mode a e d inke s, as i has been sugges ed o o he
ou comes [42]. In o de o accoun o con ounding by
hese ac o s, se e al li es yle a iables, including quali y
o he die and se e al indica o s o an o e all heal hy
li es yle and heal h consciousness, had been included in
he mul iple-adjus ed model.
Some impo an s eng hs o he p esen s udy a e i s
p ospec i e design, he use o epea ed measu emen s o
alcohol in ake du ing ollow-up, he la ge sample size o
a e y homogeneous popula ion and he good adjus men
o po en ial con ounde s. In addi ion, he high p e alence
o low- o-mode a e a e age alcohol in ake wi h almos
null p e alence o excessi e d inking oge he wi h he
p e e ence o wine consump ion o e ed a unique oppo -
uni y o in es iga e he in luence o hese wo pa icula
ac o s (ligh - o-mode a e d inking and wine consump ion),
while i limi ed ou powe o de ec associa ions be ween
hea y d inking and dep ession.
Inhe en o nu i ional epidemiology me hods, we ha e
o poin ou he possibili y o some deg ee o misclassi i-
ca ion in he die a y assessmen me hods. Howe e , we
used a FFQ ex ensi ely alida ed in Spain o he die a y
assessmen [26,43,44]. In addi ion, he co ela ion coe i-
cien in he alida ion s udy was highe o alcohol han
o mos o he nu ien s. Mo eo e , i he e is some mis-
classi ica ion i will be mo e likely non-di e en ial and,
he e o e, he associa ion would p obably be d i en
owa ds he null alue. Ano he limi a ion in ou s udy is
ha we a e no exclusi ely using a clinical diagnosis o
dep ession. P obably we a e achie ing a high speci ici y a
he expense o losing sensi i i y. Mo eo e , he e is a
possibili y ha pa e ns o alcohol consump ion may be
associa ed wi h decisions o seek ca e. I hea y d inke s
we e less likely o seek medical ca e, his could esul in
he a es o dep ession being unde -es ima ed among
hea y d inke s.
Conclusions
In conclusion, low- o-mode a e o al alcohol in ake and
speci ically wine consump ion may educe inciden de-
p ession, while hea y d inke s seem o be a highe isk.
Fu he coho s udies a e needed o con i m hese
esul s.
Addi ional iles
Addi ional ile 1: Flow cha o pa icipan s: he PREDIMED S udy.
Addi ional ile 2: Main analyses s a i ied by sex. Haza d a ios
(95% con idence in e als) o inciden dep ession acco ding o
ca ego ies o baseline daily alcohol in ake, and Rela i e isks (95%
con idence in e als) o inciden dep ession acco ding o ca ego ies
o upda ed alcohol in ake, using epea ed measu emen s o die
du ing ollow-up, s a i ied by sex. The PREDIMED S udy 2003
o 2010.
Addi ional ile 3: Fixed-e ec s models. Odds a ios (95%
con idence in e als) o a new inciden episode o dep ession, o
eco e y om an episode o dep ession, acco ding o ca ego ies o
baseline daily alcohol in ake, using ixed-e ec s models. The
PREDIMED S udy 2003 o 2010.
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Abb e ia ions
AUD: Alcohol use diso de s; CHD: Co ona y hea disease; CI: Con idence
in e al; FFQ: Food F equency Ques ionnai e; GEE: Gene alized es ima ing
equa ions; HR: Haza d a io; MET: Me abolic equi alen ask;
PREDIMED: (P e ención con Die a Medi e ánea) P e en ion wi h
Medi e anean Die ; SUN coho : Uni e si y o Na a a ollow-up S udy
(“Seguimien o Uni e sidad de Na a a”).
Compe ing in e es s
D . Es uch epo s se ing on he boa d o and ecei ing lec u e ees om
he Resea ch Founda ion on Wine and Nu i ion (FIVIN); se ing on he
boa ds o he Bee and Heal h Founda ion and he Eu opean Founda ion o
Alcohol Resea ch (ERAB); ecei ing lec u e ees om Ce ece os de España
and Sano i-A en is; and ecei ing g an suppo h ough his ins i u ion om
No a is. D . Salas-Sal adó epo s se ing on he boa d o and ecei ing
g an suppo h ough his ins i u ion om he In e na ional Nu and D ied
F ui Council; ecei ing consul ing ees om Danone; and ecei ing g an
suppo h ough his ins i u ion om E oski and Nes lé. D . A ós epo s
ecei ing paymen o he de elopmen o educa ional p esen a ions om
Mena ini and As aZeneca. D . Lamuela-Ra en ós epo s se ing on he
boa d o and ecei ing lec u e ees om FIVIN; ecei ing lec u e ees om
Ce ece os de España; and ecei ing lec u e ees and a el suppo om
PepsiCo. D . Se a-Majem epo s se ing on he boa ds o he Medi e anean
Die Founda ion and he Bee and Heal h Founda ion. D . Pin ó epo s
se ing on he boa d o and ecei ing g an suppo h ough his ins i u ion
om he Residual Risk Reduc ion Ini ia i e (R3i) Founda ion; se ing on he
boa d o Omega o ; se ing on he boa d o and ecei ing paymen o he
de elopmen o educa ional p esen a ions, as well as g an suppo h ough
his ins i u ion, om Fe e ; ecei ing consul ing ees om Abbo
Labo a o ies; ecei ing lec u e ees, as well as g an suppo h ough his
ins i u ion, om Me ck and Roche; ecei ing lec u e ees om Danone and
Es e e; ecei ing paymen o he de elopmen o educa ional p esen a ions
om Mena ini; and ecei ing g an suppo h ough his ins i u ion om
Sano i-A en is, Kowa, Unile e , Boeh inge Ingelheim, and Ka o Bio. No o he
po en ial con lic o in e es ele an o his a icle was epo ed.
Au ho s’con ibu ions
AG conduc ed he li e a u e e iew, pa icipa ed in he design o he p esen
s udy, cleaned he da a, conduc ed he main s a is ical analyses and
p epa ed he i s d a o he manusc ip . J-JB pa icipa ed in he s a is ical
analyses plan and in he design o he p esen s udy, and e ised he
manusc ip . RE ini ia ed he collabo a i e p ojec , designed da a collec ion
ools, moni o ed da a collec ion o he whole ial, e ised he manusc ip
and con ibu ed o he in e p e a ion o indings. AS-V conduc ed pa o he
li e a u e e iew, cleaned and analyzed da a, pa icipa ed in he design o
he p esen s udy, e ised he manusc ip and con ibu ed o he
in e p e a ion o indings. JS-S implemen ed he ial in Reus, moni o ed he
da a collec ion and e ised he manusc ip . PB-C pa icipa ed in he
implemen a ion o he ial in Pamplona, pa icipa ed in he design o he
da a collec ion ools and e ised he manusc ip . EG-G implemen ed he ial
in Málaga, moni o ed he da a collec ion and e ised he manusc ip . M-IC
implemen ed he ial in Ba celona, moni o ed he da a collec ion and
e ised he manusc ip . DC implemen ed he ial in Valencia, moni o ed he
da a collec ion, and e ised he manusc ip . MF implemen ed he ial in
Palma de Mallo ca, moni o ed he da a collec ion and e ised he
manusc ip . FA implemen ed he ial in Vi o ia, moni o ed he da a
collec ion and e ised he manusc ip . JL implemen ed he ial in Se illa,
moni o ed he da a collec ion and e ised he manusc ip . R-ML-R
implemen ed he ial in Ba celona, moni o ed he da a collec ion and
e ised he manusc ip . JW pa icipa ed in he design o he p esen s udy,
moni o ed he da a collec ion and e ised he manusc ip . XP implemen ed
he ial in Ba celona, moni o ed he da a collec ion and e ised he
manusc ip . LS-M implemen ed he ial in Las Palmas de G an Cana ia,
moni o ed he da a collec ion and e ised he manusc ip . M-AM-G ini ia ed
he collabo a i e p ojec , designed da a collec ion ools, moni o ed da a
collec ion o he whole ial, implemen ed he ial in Pamplona, supe ised
all he s eps in he s a is ical analyses and p epa a ion o he manusc ip , and
con ibu ed o he in e p e a ion o indings. He is he gua an o . All au ho s
c i ically e ised he manusc ip o impo an in ellec ual con en and
app o ed he inal e sion o be submi ed o publica ion.
Acknowledgemen s
We hank he o he membe s o he PREDIMED G oup:
Uni e si y o Na a a, Depa men o P e en i e Medicine and Public Heal h,
Pamplona, Spain: E. Toledo, M. Bes-Ras ollo, A. Sánchez-Tain a, B. Sanjulián, E.
Goñi, M. Ma ques, A. Ga cía-A ellano, I. Zazpe, J. Bas e a-Go a i, E. H.
Ma ínez-Lapiscina.
Uni e si y o Na a a, P ima y Ca e Cen es, Pamplona, Spain: M. Se ano-
Ma ínez, J. Díez-Espino, N. O uño, N. Be ade, V. Ex eme a-U abayen, C. A oyo-
Azpa, L Ga cía-Pé ez, J. Villanue a Telle ía, F. Co és Ugalde, T. Sag edo A ce,
Mª D. Ga cía de la Noceda Mon oy, Mª D. Viga a López, Mª T. A ceiz Campo,
A.U asunSampe ,MªV.Gue oRubioandB.Chu ioBe aza.
Uni e si y o Na a a, School o Pha macy, Pamplona, Spain: J. A. Ma inez, A.
Ma í.
Hospi al Clinic, Ins i u d’In es igacions Biomèdiques Augus Pi i Sunye ,
Ba celona, Spain: M. Se a, A. Pé ez-He as, C. Viñas, R. Casas, L. de San ama ía,
S. Rome o, J. M. Baena, M. Ga cía, M. Olle , J. Ama , I. Duaso, Y. Ga cía, C.
Iglesias, C. Simón, Ll. Quinza os, Ll. Pa a, M. Li oz, J. Bena en , J. Clos, I. Pla,
M. Amo ós, M. T. Bone , M. T. Ma in, M. S. Sánchez, J. Al i uba, E. Manzano,
A. Al és, M. Co án, C. Valls, A. Sala-Vila and M. Doménech.
Uni e si y Ro i a i Vi gili, Reus, Spain: M. Bulló, R. González, C. Molina, F.
Má quez, N. Babio, M. So li, J. Ga cía Roselló, F. Ma in, R. To , A. Isach, B.
Cos a, J. J. Cab é and J. Fe nández-Balla .
Ins i u e de Rece ca Hospi al del Ma , Ba celona, Spain: S. Tello, J. Vila, M. Fi ó,
H. Sch öde , R. De la To e, D. Muñoz-Aguayo, R. Elosúa, J. Ma uga and M.
Fe e .
Uni e si y o Valencia, Valencia, Spain: P. Ca asco, R. Osma, M. Guillén, P.
Guillem-Saiz, O. Po olés, V. Pascual, C. Rie a, J. Valde ama, A. Se ano, E.
Láza o, A. Sanma ín, A. Gi bés, V. San ama ía, C. Sánchez, Z. Plá, E. Sánchez,
C. O ega-Azo ín, J. I. González and C Saiz.
Uni e si y Hospi al o Ala a, Vi o ia, Spain: I. Sala e ía, T. del Hie o, J. Algo a,
S. F ancisco, A. Alonso, J. San Vicen e, E. Sanz, I. Felipe, A. Alonso Gómez and
A. Loma-Oso io.
Uni e si y o Málaga, Málaga, Spain: R. Bení ez Pon , M. Bianchi Alba, J.
Fe nández-C ehue Na ajas, R. Gómez-Huelgas, J. Ma ínez-González, V.
Velasco Ga cía, J. de Diego Salas, A. Baca Oso io, J. Gil Za zosa, J. J. Sánchez
Luque and E. Va gas López.
Ins i u o de la G asa, Consejo Supe io de In es igaciones Cien í icas, Se illa,
Spain: J. Sánchez Pe ona, E. Mon e o Rome o, A. Ma ín Rod íguez and V.
Ma ín A anz.
Ins i u e o Heal h Sciences IUNICS, Uni e si y o Balea ic Islands, and
Hospi al Son Espases, Palma de Mallo ca, Spain: M. Ga cía-Valdueza, M.
Moñino, A. P oenza, R. P ie o, G. F on e a, M. Gina d, F. Fiol, A. Jo e and J.
Ga cía.
Depa men o Family Medicine, P ima y Ca e Di ision o Se illa, Se illa,
Spain: M. Leal, E. Ma ínez, J. M. San os, M. O ega-Cal o, P. Román, F. José
Ga cía, P. Iglesias, Y. Co chado, E. Mayo al and C. Lama.
School o Pha macy, Uni e si y o Ba celona, Ba celona, Spain: M. C. López-
Saba e , A. I. Cas ello e-Ba gallo, A. Medina-Remón and A. T esse a-Rimbau.
Uni e si y o Las Palmas de G an Cana ia, Las Palmas, Spain: J. Ál a ez-Pé ez,
E. Díez Bení ez, I. Bau is a Cas año, I. Maldonado Díaz, F. Sa miendo de la Fe,
C. Ruano, M. J. He nández, B. Macías Gu ié ez, P. Hen íquez and I. Cas o.
Hospi al Uni e si a io de Bell i ge, Hospi ale de Llob ega , Ba celona, Spain:
E. de la C uz, A. Gale a, Y. Sole , F. T ías, I. Sa asa, E. Pad es and E. Co bella.
P ima y Ca e Di ision, Ca alan Ins i u e o Heal h, Ba celona, Spain: C.
Cabezas, E. Vinyoles, M. A. Ro i a, L. Ga cía, G. Flo es, J. M. Ve dú, P. Baby, A.
Ramos, L. Mengual, P. Rou a, M. C. Yus e, A. Gua ne , A. Ro i a, M.I.
San ama ía, M. Ma a, C. de Juan and A. B au.
O he in es iga o s o he PREDIMED ne wo k: M. T. Mi ja ila (Uni e si y o
Ba celona), M. P. Po illo (Uni e si y o Basque Coun y), G. Sáez (Uni e si y o
Valencia) and J. Tu (Uni e si y o Balea ic Islands).
AG hanks he Spanish Go e nmen o he FPU ellowship ecei ed.
Au ho de ails
1
Depa men o P e en i e Medicine and Public Heal h, Medical School-
Clinica Uni e sidad de Na a a, Pamplona, Spain.
2
School o Medicine,
Uni e sidad Eu opea de Mad id, Mad id, Spain.
3
CIBER Fisiopa ología de la
Obesidad y Nu ición (CIBERObn), Ins i u o de Salud Ca los III, Mad id, Spain.
4
Depa men o In e nal Medicine, Hospi al Clinic, Uni e si y o Ba celona,
Ba celona, Spain.
5
Depa men o Clinical Sciences, Uni e si y o Las Palmas
de G an Cana ia, Las Palmas de G an Cana ia, Spain.
6
Human Nu i ion Uni ,
IISPV, Uni e si a Ro i a i Vi gili, Reus, Spain.
7
Spain P ima y Ca e, Se icio
Gea e al. BMC Medicine 2013, 11:192 Page 8 o 10
h p://www.biomedcen al.com/1741-7015/11/192