Treatment with combined exercise in patients with resistant major depression (TRACE-RMD): study protocol for a randomised controlled trial

I ia e‑Yolle e al. T ials (2024) 25:827
h ps://doi.o g/10.1186/s13063‑024‑08685‑7
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T ials
T ea men wi hcombined exe cise
inpa ien s wi h esis an majo dep ession
(TRACE‑RMD): s udy p o ocol o a andomised
con olled ial
Nago e I ia e-Yolle 1,2,3, José E xaniz-Oses4,5, C is obal Pa ón-Na ajas1,2,3, Mikel Tous-Espelosin4,5,
Ped o M. Sánchez-Gómez2,3,6, Sa a Maldonado-Ma ín4,5*, Ana B. Yolle -Elbu go1 and
Edo a Elizaga a e-Zabala1,2,3
Abs ac
Backg ound A ound 40% o people wi h majo dep essi e diso de (MDD) expe ience mode a e emission,
wi h he emainde mee ing he c i e ia o esis an majo dep ession (RMD). I has been shown ha exe cise
has a low- o-mode a e e ec on MDD, bu he e is a lack o e idence on exe cise in e en ions in RMD pa ien s. The
p ima y pu pose o he p oposed s udy will be o in es iga e he e ec o a 12-week supe ised combined exe cise
p og am on dep essi e symp oms in people wi h RMD compa ed o a ea men -as-usual (TAU) g oup.
Me hod This andomised, single-blind, con olled expe imen al ial will include 70 adul s (≥ 18 yea s old) wi h RMD.
Pa icipan s andomised o an exe cise in e en ion, o a TAU g oup will be assessed a baseline and a e a h ee-
mon h in e en ion pe iod. The p ima y a iable will be pa icipan s’ dep essi e symp oms measu ed wi h he Mon -
gome y-Asbe g Dep ession Ra ing Scale. Seconda y ou come a iables will include ca dio espi a o y i ness (peak
oxygen up ake h ough peak ca diopulmona y exe cise es ), body composi ion (bioimpedance and an h opome ic
a iables), physical ac i i y le el ( he In e na ional Physical Ac i i y Ques ionnai e), heal h- ela ed quali y o li e ( he
Sho Fo m-36 Heal h Su ey), unc ional ou come ( he Sheehan Disabili y Scale and Quali y o Li e in Dep ession
Scale), o e all disease se e i y ( he Clinical Global Imp ession Scale-Se e i y o Illness), and biochemical a iables (a
as ing blood sample).
Discussion This s udy will y o answe whe he a supe ised co-adju an combined (ae obic and esis ance ain-
ing) exe cise p og am will help he p ognosis o his popula ion wi h RMD.
T ial egis a ion ClinicalT ials.go NCT05136027. Las public elease on 12/13/2023.
Keywo ds Randomised con olled ial, Resis an majo dep ession, Exe cise, Quali y o li e, Combined aining
*Co espondence:
Sa a Maldonado-Ma ín
[email p o ec ed]
Full lis o au ho in o ma ion is a ailable a he end o he a icle
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I ia e‑Yolle e al. T ials (2024) 25:827
In oduc ion
Majo dep essi e diso de (MDD) is one o he mos
p e alen men al diso de s wo ldwide and one o he
mos disabling, a ec ing mo e han 300 million peo-
ple globally [1]. Thus, MDD is a complex mul i ac o ial
condi ion ha includes complex pa hophysiology and
c ea es neu al and neu o ansmi e in lamma ion [1,
2].
In addi ion o dep essi e symp oms, people wi h MDD
end o lead an unheal hy li es yle, including a lack o
physical ac i i y, seden a y beha iou , smoking, abuse
o alcohol, and poo die , esul ing in a ious ca dio-
ascula - ela ed diseases (e.g. co ona y hea disease,
obesi y, diabe es melli us ype 2, and s oke) [3]. Physio-
logically, people su e ing om MDD a e associa ed wi h
inc eased immune sys em ac i a ion, leukocy e unc ion,
and elease o p oin lamma o y cy okines such as in e -
leukins (IL) 1, 2, and 6 [1]. The e o e, he combina ion o
pha macological ea men (i.e. a a ie y o an idep es-
san s) and psychological he apies o he ea men o
MDD is insu icien . In his sense, a ound 40% o peo-
ple wi h MDD expe ience mode a e emission, wi h
he emainde mee ing he c i e ia o esis an majo
dep ession (RMD) [4].
The ypical ea men o his popula ion consis s o
a pha macological in e en ion using i s - and second-
gene a ion an idep essan d ugs ha ac on he b ain
synapse o inc ease he bioa ailabili y o amines (i.e.
se o onin, no ad enaline, and dopamine) [5]. Howe e ,
only one- hi d o people achie e emission a e ini ial
ea men [5]. Hence, RMD is de ined as an inadequa e
esponse o a leas wo di e en an idep essan s o
app op ia e dose and du a ion [6]. Gi en his bleak ou -
look, se e al non-pha macological s a egies ha e been
conside ed as possible co-adju an in e en ions o help
imp o e he p ognosis and emission a es o RMD, such
as neu osu gical in e en ion, soma ic he apies, elec o-
con ulsi e he apy, o e en adjunc i e s a egies, among
which exe cise is one o he mos impo an [7]. I has
been shown ha exe cise has a low- o-mode a e amelio-
a ion e ec on MDD, wi h esponse a es compa able o
mains eam he apies like an idep essan medica ion and
cogni i e beha iou al he apy [1, 8].
The la es Wo ld Heal h O ganiza ion guidelines on
physical ac i i y and seden a y beha iou include e i-
dence-based public heal h ecommenda ions o peo-
ple li ing wi h ch onic condi ions like men al diso de s.
Thus, adul s should pe o m 150–300min pe week o
mode a e-in ensi y physical ac i i y and wo days o
muscle-s eng hening ac i i y [9]. Howe e , con o e sy
s ill exis s abou he FITT ( equency, in ensi y, ime, and
ype) p inciple and he la es scien i ic ad ances in exe -
cise aining o people wi h RMD.
In mos s udies conduc ed wi h his popula ion, he
exe cise in e en ions included 1h pe session, wo days
pe week, and mo e han 10weeks o endu ance in e -
en ion [10, 11], pe o med on a cycle e gome e o
eadmill [10, 12]. Only one s udy conduc ed a combined
in e en ion, including endu ance and esis ance aining
[12]. P e ious s udies ha e shown ha low- o-mode a e
in ensi y aining is an e icien me hod o imp o e di -
e en ou comes like ca dio espi a o y i ness (CRF) and
body mass index (BMI) in adul popula ions wi h ch onic
diseases, especially o indi iduals wi h a low ini ial le el
o ae obic i ness [13, 14].
Conside ing he abo e, he e we p opose he TRACE-
RMD s udy o in es iga e he e ec s o a 12-week
supe ised combined exe cise p og am (i.e. ae obic and
esis ance exe cises in he same session) o people wi h
RMD in compa ison wi h a ea men -as-usual (TAU)
con ol g oup doing occupa ional ac i i y sessions wi h
he same equency and du a ion as he exe cise g oup.
Thus, he main aim o his andomised con olled ial
will be o analyse he e ec s o a combined exe cise
p og am on dep essi e symp oms compa ed o a TAU
g oup. The seconda y objec i es will be (1) o analyse he
p og am’s e ec s on CRF, body composi ion, and bio-
chemical le els and (2) o de e mine changes in he unc-
ional ou come, o e all disease se e i y, and quali y o li e
o pa icipan s.
Me hods
S udy design, e hical app o al, and egis a ion
The TRACE-RMD s udy will be a andomised, single-
blind (i.e. medical specialis s will e alua e he psychi-
a ic a iables) con olled expe imen al ial wi h wo
pa allel g oups, supe io i y ial [15]. The s udy p o ocol
was w i en pe he S anda d P o ocol I ems: Recom-
menda ions o In e en ional T ials (SPIRIT) guidelines
[16] and he upda ed SPIRIT 2024 and CONSORT 2024
epo ing guidelines [17], aiming o imp o e he quali y
o he in ended andomised clinical ial. This p ojec is
unded by he “III Con oca o ia In amu al de la Fun-
dación Vi al Fundazioa – IIS BIOARABA” and he Men-
al Heal h Ne wo k o Ála a, wi h a single pu pose o
inancial assis ance.
Pa icipan s: ec ui men andselec ion c i e ia
Specialised psychia is s om he Resis an Dep ession
Uni o he Ála a Psychia ic Hospi al and Ála a Men-
al Heal h Ne wo k (Basque Coun y, Spain) will ec ui
70 adul s wi h RMD, which p o ides psychia ic ca e o
he popula ion li ing in he communi y and encou age
pa icipa ion by explaining he bene i s o exe cise as an
adju an p og amme in hei ea men . Be o e accep ing
w i en in o med consen om all eligible pa icipan s,
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I ia e‑Yolle e al. T ials (2024) 25:827
psychia is s and specialised nu ses will be app oached
o ques ions. The inclusion and exclusion c i e ia o he
TRACE-RMD s udy a e shown in Table1.
Pa icipan s will be ee o wi hd aw om he s udy a
any ime. The pa icipan may no con inue in he s udy
o he ollowing easons: (1) ailu e o main ain 80%
compliance wi h aining sessions (minimum 19 ses-
sions); (2) missing mo e han wo consecu i e aining
sessions; (3) he pa icipan ’s condi ion o disease p o-
g esses; (4) he pa icipan expe iences a se e e ad e se
e en (e.g. angina, dyspnoea, dizziness) ha equi es dis-
con inua ion o wi hd awal om he s udy in acco dance
wi h he s udy p o ocol; o (5) p egnancy.
Randomisa ion
A e he in o med consen is accep ed and signed, he
pa icipan s will be included in he ial by being gi en
a ial-speci ic anonymous iden i ica ion (i.e. TRACE-
01) numbe (ID) o ensu e con iden iali y and acili a e
possible p ospec i e me a-analyses. Alloca ion consign-
men will be pe o med by a echnician om Bioa aba
Heal h Resea ch Ins i u e (h p:// alea o iza cion. bioa
aba. o g/) using he echnique o s a i ied andomisa ion
(1:1) by sex (men/women) and dep essi e symp oms. The
pa icipan s will be andomised o one o he wo in e -
en ion g oups: (1) he exe cise (EX) g oup and (2) he
TAU g oup. Exe cise physiologis s will be esponsible o
in o ming each pa icipan o he g oup in which hey
will pa icipa e. Figu e1 p esen s a low diag am o he
s udy p ocess.
Ou comes andmeasu emen s
Da a collec ion will be based on an assessmen p o-
ocol o ga he ing da a on physical, clinical, and bio-
chemical a iables. Assessmen s used in he p o ocol
will be e alua ed be o e (T0) and a e a 12-week in e -
en ion pe iod (T1). Expe ienced specialis s in psy-
chia y and nu sing om he Psychia ic Hospi al o
Ála a will assess and collec clinical da a. The physical,
physiological and unc ional a iables will be e alua ed
and eco ded by physical spo s educa o s wi h o e
20 yea s o expe ience who will ain hei doc o al,
unde g adua e, and pos g adua e s uden s. Pa icipan s
om he wo g oups will be assessed concu en ly.
Sociodemog aphic da a (including pa icipan sex, age,
s a e o con i ence, p o essional s a us, d ug and smok-
ing s a us, age o onse o illness, numbe o hospi ali-
sa ions, da e o las hospi alisa ion, medica ion in ake,
and ea men du a ion) will be collec ed be o e he
baseline assessmen . Measu emen s will be pe o med
in h ee sepa a e isi s acco ding o he sequence:
– Visi 1: unc ional ou come and quali y o li e wi h
ques ionnai es.
– Visi 2: an h opome y, body composi ion and ca -
diopulmona y exe cise es (CPET).
– Visi 3: as ing blood sample.
The p ima y ou come (dep essi e symp oms) will be
measu ed wi h he Mon gome y-Asbe g Dep ession
Ra ing Scale (MADRS) using he alida ed Spanish e -
sion [18]. Seconda y ou come a iables will include
CRF, body composi ion, biochemical and unc ional
ou comes, and quali y o li e. The SPIRIT igu e show-
ing he ime poin s o assessmen s and in e en ion is
shown in Fig.2.
The MADRS is a clinical in e iew wi h ex ended
ph ased ques ions abou symp oms o dep ession and
anxie y. The ques ionnai e has en di e en i ems abou
dep ession. Adding up sco es can be ob ained be ween
Table 1 Inclusion and exclusion c i e ia o he TRACE-RMD s udy
≥ g ea e han o equal o, RMD esis an mayo dep ession
Inclusion c i e ia
- ≥ 18 yea s old
- Pa ien s li ing in he communi y o hospi alised pa ien s. In he wo cases, he RMD diagnosis is de ined as he pe son who ecei es he ea men
does no ha e a emission, wi h a poo o unsa is ac o y esponse o a leas wo adequa e (i.e. op imal dosage and du a ion) di e en an idep essan s.
Howe e , p e ious esea ch s udies ha e demons a ed he lack o consensus c i e ia in de ining RMD [6].
- T ea men - esis an dep ession is de ined as esis ance o wo o mo e an idep essan s
- W i en in o med consen has been signed
Exclusion c i e ia
- Schizoph enia o o he psychoses
- P esence o imminen suicidal isk
- Uns able o inadequa ely con olled medical illnesses (in acu e pa hology si ua ions)
- Ac i e subs ance use diso de
- Como bidi y wi h o he psychia ic pa hologies cons i u es he main ocus o ea men
- Cogni i e impai men ancho ed by he Mon eal Cogni i e Assessmen scale < 26/30
- Inabili y o pe o m exe cise seconda y o os eoa icula , ca dio ascula o me abolic di icul ies
- Pe o ming exe cise con inuously as a egula p ac ice
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I ia e‑Yolle e al. T ials (2024) 25:827
0 (ze o; absence o dep ession) and 60 (majo le el o
dep ession) [18].
Fo e alua ing unc ionali y, he Sheehan Disabili y
Scale (SDS) [19] and he Spanish e sion o he Quali y
o Li e in Dep ession Scale (QLDS) [20] will be used. The
copy igh license ag eemen o he SDS was ob ained
h ough D . Da id V. Sheehan, and i included a Spanish
linguis ic alida ion. The SDS is a subjec i e scale wi h
h ee i ems (social, amily, and wo k) e alua ing he inca-
paci y o dep ession [21], and he QLDS is a dep ession-
speci ic quali y o li e scale based on he possibili y and
capaci y o he indi idual o sa is y he pa icula needs
[20]. The o e all disease se e i y will be measu ed using
he Clinical Global Imp ession Scale-Se e i y o Illness
(CGI-SI). The CGI-SI is a desc ip i e, he e o-applied
scale ha p o ides quali a i e in o ma ion on he se e -
i y o he clinical condi ion and he change expe ienced
by he pa ien conce ning he baseline condi ion in h ee
di e en measu es (i.e. illness se e i y, global imp o e-
men , and e icacy index) [22].
An h opome y will include s a u e (SECA 213, Ham-
bu g, Ge many), o al body mass (SECA 869, Hambu g,
Ge many), BMI calcula ed as o al body mass (kg)/s a -
u e (m2), and wais and hip ci cum e ences calcula ed
wi h wais - o-hip a io (SECA 200, Hambu g, Ge many).
All measu emen s ollow he In e na ional Socie y o
he Ad ancemen o Kinan h opome y guidelines [23].
Fu he mo e, bioelec ical impedance analysis will es i-
ma e a - ee mass, o al body wa e , and a mass (Tan-
i a, BF 350, and Tani a, BC-418 MA, Ams e dam, he
Ne he lands).
The In e na ional Physical Ac i i y Ques ionnai e
(IPAQ) will assess physical ac i i y le el and seden a y
beha iou . This ques ionnai e has se en i ems, and he
pa icipan should espond on hei own basis o e he
p io 7days [24]. The Spanish e sion o he Sho Fo m-
36 Heal h Su ey (SF-36) will assess pa icipan s’ heal h-
ela ed quali y o li e. The SF-36 is a sho ques ionnai e
wi h 36 i ems o eigh dimensions o i ems, including
physical unc ioning, social unc ioning, ole limi a ions
Fig. 1 Flow diag am o he TRACE-RMD s udy
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I ia e‑Yolle e al. T ials (2024) 25:827
a ibu ed o physical p oblems, ole limi a ions a ib-
u ed o emo ional issues, men al heal h, i ali y, pain, and
gene al heal h pe cep ion [25].
The CRF assessmen will in ol e a symp om-limi ed
CPET on a bike e gome e (Lode Excalibu , G oningen,
he Ne he lands). The p o ocol will commence a 40
W, wi h g adual inc emen s o 10 W pe minu e un il
exhaus ion while con inuously moni o ing an elec oca -
diog am. The gas analyse (E go Ca dMedi-so S.S, Bel-
gium Re . USM001 V1.0) will unde go calib a ion be o e
each es . Peak oxygen up ake (VO2peak) will be de ined
as he highes oxygen consump ion alue achie ed a e
he es . Peak e o will be acknowledged when mee -
ing a leas wo o mo e o he ollowing c i e ia: pa ici-
pan a igue (Bo g scale > 18), espi a o y exchange ≥ 1.1,
a ainmen o > 85% o p edic ed maximum hea a e
(HR), and no inc ease in VO2 and/o HR wi h escala ing
wo kload [26].
A e each minu e, he subjec i e sensa ion o exe ion
will be documen ed using he o iginal Bo g scale [27].
Blood p essu e (BP) will be assessed a wo-minu e in e -
als h oughou he es . Ven ila o y h esholds (VTs)
will be e alua ed h ough s anda dised me hodologies
employing V-slope and en ila o y equi alen s (EqV).
The i s en ila o y h eshold (VT1) will be de e mined
when he in lexion poin in he ca bon dioxide p oduc-
ion (VCO2) e sus VO2 slope ansi ions om less han
1 o g ea e han 1. Al e na i ely, i can be iden i ied as
he nadi in he EqV a io o VO2 e sus wo kload. The
second en ila o y h eshold (VT2) will be pinpoin ed as
he nadi in he EqV/VCO2 a io e sus wo kload [26].
A e comple ing he es , he pa icipan will es on he
bicycle o an addi ional 5min o eco d eco e y a i-
ables. All absolu e and ela i e c i e ia o concluding he
es will be duly conside ed. The in ensi y anges will be
indi idually ailo ed based on HR o es ablish ligh ( ang-
ing om a es ing HR alue o an HR alue o he VT1)
and mode a e (HR alue be ween VT1 and VT2) in en-
si y ca ego ies: speci ically, R1—ligh o mode a e in en-
si y wi h HR alues below VT1; R2—mode a e- o-high
in ensi y wi h HR alues be ween VT1 and VT2; and R3—
in ense- o-se e e in ensi y wi h HR alues abo e VT2 up
o peak HR.
Biochemical p o iles will be de e mined wi h a as -
ing blood sample (10 mL) collec ed a he hospi al
o each pa icipan a e an o e nigh as , including
Fig. 2 The SPIRIT igu e shows an o e iew o he assessmen schedule a baseline and ollow-up in he TRACE-RMD s udy

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he ollowing pa ame e s: haemoglobin, haema oc i ,
o al choles e ol, high-densi y lipop o ein choles e ol,
low-densi y lipop o ein choles e ol, iglyce ides, glu-
cose, insulin, aspa a e ansaminase, alanine ansami-
nase, gamma-glu amyl ans e ase, C- eac i e p o ein,
u ic acid, c ea inine, sodium, po assium, and albumin.
HOMA-IR will be used o e alua e insulin esis ance
(i.e. as ing se um insulin [μU/mL] × as ing plasma glu-
cose [mg/dL]/405) [28]. Mo eo e , cy okine le els in
IL-1, IL-6, and IL-10 plasma le els will be measu ed ia
enzyme immunoassays.
S udy in e en ion
The pa icipan s en olled in he EX g oup will unde go a
12-week exe cise p og am ( wo non-consecu i e days pe
week) unde he supe ision o exe cise specialis s a ou -
o -hospi al acili ies (i.e. he Physical Ac i i y o Heal h
Resea ch Cen e ). All sessions will s a and end wi h BP
measu emen s, and exe cise in ensi y will be moni o ed
by HR moni o s (Pola Elec o, Kempele, Finland) and
h ough he o iginal Bo g scale (6–20). Each session will
include a 10min wa m-up and a 10min cool-down wi h
s e ching. The main pa o he session will consis o a
ou -pa ci cui o 10min each: (1) a low- olume and
low-in ensi y in e al aining (LV-LIIT) exe cise on he
bicycle (Table2); (2) s eng h- esis ance exe cises (elas ic
bands, own body weigh , dumbbells (Addi ional ile1));
(3) an LV-LIIT exe cise on he bicycle (Table2); and (4)
lumbopel ic s eng hening exe cises (Addi ional ile1).
Du ing he sessions, he powe and speed o he bike will
be adjus ed o achie e he a ge HR. In he LV-LIIT exe -
cise, pa icipan s will wa m up o 2min and hen engage
in six in e als o 15 s a R2 in e spe sed wi h 1-min
in e als a R1, inishing wi h 2min o cool-down a R1
(Table2). In he esis ance wo kou , he pa icipan s will
pe o m a ime-based ci cui (30s pe exe cise, wi h 30s
es ) o 10 s eng h- esis ance exe cises, including bo h
uppe and lowe body, co e ing he main muscle g oups
and coo dina ed wi h b ea hing. In he lumbopel ic
s eng hening wo kou , he pa icipan s will ca y ou six
exe cises (20 epe i ions wi h 20s o es be ween each
exe cise), including he an e io and pos e io muscula-
u e (Addi ional ile1). Some s a egies will be used o
achie e adhe ence, such as indi idualised a en ion while
exe cising and elephone calls ollowing missed sessions.
The TAU g oup will conduc a s anda d p ac ice and
con inue wi h hei egula ea men plus occupa ional
ac i i ies (inpa ien ) o he same du a ion as he in e -
en ion in he EX g oup. Due o RMD, i is no necessa y
o ins uc pa icipan s no o engage in any o he ac i -
i y in ol ing exe cise because he di icul y is o in ol e
hem in he p ojec . To p omo e e en ion in he p ojec ,
a e comple ion o he pos -in e en ion assessmen s, all
pa icipan s a e o e ed an exe cise p og amme wi hin
he hospi al (un ela ed o he esea ch).
In case o ad e se e en s will be eco ded and epo ed
o he co esponding E hics Commi ee.
Da a managemen
Da a managemen will comply wi h he egula ions o he
Bioa aba Heal h Resea ch Ins i u e. All da a eco ding
will be ca ied ou by he lead esea ch psychia is (NIY)
and he pe sons esponsible o he exe cise p og amme
(JEO and MTE) wi h a pape -based egis y. The pape -
based da abase will be coded, egis e ed, and s o ed in a
cloud pla o m, and only he pe sons esponsible o he
esea ch will ha e access o i . Communica ion among
specialis s (psychia y, nu sing, and spo s physical edu-
ca o s) will be cons an o ensu e ha once he psychia-
is ec ui s, he nu se will ca y ou he ques ionnai es
he ollowing week, and he spo s physical educa o s
will assess he physical and physiological condi ions.
Bo h g oups (hospi al and uni e si y) will mee e e y
h ee mon hs o iden i y possible e o s and e alua e
he s udy’s p og ess. The e hical commi ee will ask o a
memo y epo once a yea .
Upon comple ion o he s udy, he esul s will be pub-
lished and p esen ed o social media, academics, and
clinical ins i u ions. Likewise, esea ch a icles will be
submi ed o pee - e iewed jou nals and p esen ed a
ele an scien i ic con e ences. The da a will be a ailable
by publishing on open da a eposi o ies. We ha e no con-
ac ual ag eemen s ha limi in es iga o s’ access.
Sample size es ima ion
We ha e conduc ed a p e ious pilo s udy wi h 18 pa -
icipan s diagnosed wi h RMD in a single supe ised
exe cise g oup (12 weeks, 2 days/week). Following he
in e en ion (da a no ye published), no signi ican
changes (P > 0.05) we e ound in he body composi ion,
main CRF physiological a iables, and biochemical p o-
ile. Howe e , ega ding clinical symp oms, MADRS
Table 2 Exe cise in e en ion h ough low-in ensi y in e al
aining on a cycle e gome e
P o ocol
Mode a e-in ensi y in e al
aining Low-in ensi y in e al aining
Weeks Volume
(min) In ensi y
(%HR es)Weeks Volume (min) In ensi y
(%HR es)
1–4 3 60 1–4 17 50
5–8 3 65 5–8 17 55
9–12 3 70 9–12 17 60
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I ia e‑Yolle e al. T ials (2024) 25:827
(Δ = − 27.2%; P = 0.021), CGI-S (Δ = − 25.3%; P = 0.006),
and SDS (Δ = − 22%; P = 0.046) alues dec eased; and he
domains o heal h- ela ed QoL, gene al heal h (Δ = 50.5%;
P = 0.017), i ali y (Δ = 41.4%; P = 0.045), social unc ion-
ing (Δ = 76.5%; P = 0.008), and men al componen sum-
ma y (Δ = 24.9%; P = 0.024) alues inc eased. Thus, based
on his p e ious pilo s udy wi h he same popula ion, o
achie e a powe o 80% whe e di e ences in dep essi e
symp oms (measu ed by he MADRS) a e de ec ed a e
he exe cise in e en ion, ha ing a signi icance o 5%, a
e e ence mean o 29.13 ± 12.2 uni s, an expe imen al
g oup mean o 22.23 uni s, a s anda d de ia ion be ween
bo h g oups o 9.61, and an expec ed di e ence o 2.5
uni s, 31 pa ien s pe g oup will be needed. I we assume
a 10% loss a e, 35 pa ien s pe g oup will be equi ed,
wi h a o al sample o 70 pa icipan s.
S a is ical analysis
A gene al desc ip i e analysis o he sample will be
pe o med o assess baseline homogenei y. The Kol-
mogo o –Smi no es will de e mine he no mali y o
quan i a i e a iables, and esul s will be exp essed as
means and s anda d de ia ions o as median alues and
in e qua ile anges in he case o non-no mal dis ibu-
ions. Quali a i e a iables will be exp essed as equen-
cies and pe cen ages. S uden ’s - es o ela ed samples
will be ca ied ou o assess he impac o he in e en-
ion on quan i a i e a iables. A nonpa ame ic analogue
Wilcoxon will be chosen i i does no mee no mali y
c i e ia. A co a ia e analysis (ANCOVA) will e alua e
change a e he in e en ion, conside ing he wo EX
and TAU g oups (i.e. independen a iable). The magni-
ude o he di e ences will be assessed using 95% con i-
dence in e als and Hedges’s g e ec sizes.
Du ing he de elopmen o he s udy, de ia ions om
he p o ocol may a ise. In ha case, he sponso will
in o m he unde using a b each epo o m, and he
co esponding changes will be pe o med in he clinical
ial egis y. The s a is ical analysis will be pe o med ia
in en ion- o- ea and p o ocol o manage hese si ua-
ions wi hin he s udy.
The TRACE-RMD s udy does no ha e a da a moni-
o ing commi ee, and he E hical Commi ee does no
equi e i , gi en he p ojec is unde cons an e iew by
he psychia y specialis s.
No in e im analyses a e planned.
Discussion
This s udy will be he i s clinical ial o explo e he
e icacy o a combined exe cise in e en ion as a po en-
ial co-adju an o pha macological ea men in
pa ien s wi h an RMD diagnosis. Recen me a-analyses
ha e shown ha di e en ypes and dose- esponses o
exe cises like walking, ae obic aining, Yoga, Qigong,
esis ance aining, and Tai Chi ha e e ec i ely alle i-
a ed dep essi e symp oms in olde adul s [29], and adul s
in gene al [30]. The e o e, since RMD popula ions can
be esis an o wo o mo e an idep essan s [6], exe cise
in e en ions should be conside ed an e ec i e adju an
p og am in he ea men o RMD.
In his sense, he app op ia e FITT p inciple o exe -
cise in e en ions emains unclea , and con o e sy exis s
[31, 32]. Mo eo e , al hough a signi ican pe cen age o
in e en ions a e ae obically o ien ed, a ecen me a-
analysis e ealed mode a e an idep essan e ec s o
s eng h aining in people wi h a diagnosis o dep ession
o dep essi e symp oms [33]. The e o e, combined ain-
ing (i.e. ae obic + esis ance aining in he same session)
could be conside ed a powe ul op ion o in es iga e in
people wi h RMD. Thus, p e ious s udies ha e imple-
men ed and analysed exe cise in e en ions in people
wi h RMD [11, 10, 34, 12]. While hese in e en ions ha e
shown imp o emen s in psychia ic a iables, enhanc-
ing psychopa hological symp oms like dep ession, unc-
ionali y, and e en quali y o li e, none has implemen ed
a combined exe cise aining in e en ion o analysed
po en ial physical, objec i e physiological, and biochemi-
cal imp o emen s in his popula ion. In his ega d, gi en
ha he imp o emen in CRF h ough exe cise aining
has led o enhanced heal h and educed mo ali y in peo-
ple wi h se e e men al illness [35], o analyse his a iable
is c ucial.
Fu he mo e, he biochemical analysis will p o ide he
oppo uni y o examine IL-6 and IL-1, which ha e been
associa ed wi h he onse o p oin lamma o y in lam-
ma ion and a e pa icula ly ele an in he b ain [36–
38]. In line wi h his, pe iphe al cy okines can c oss he
blood–b ain ba ie and each he cen al ne ous sys-
em, p o oking neu oin lamma ion, which migh igge
psychia ic diso de s such as dep ession [39]. The e o e,
analysing hese ILs will be pe inen , as exe cise in e en-
ions ha e been shown o dec ease IL-6 le els [40]. O e -
all, his esea ch will p o ide u he in o ma ion and
build upon p e ious indings ega ding a co-adjunc i e
s a egy (combined exe cise aining) in indi iduals diag-
nosed wi h RMD.
T ial s a us
The ial was ini ially eleased as a pilo s udy (no clini-
cal ial) on 24 h No embe 2021 ( e sion 1). The p esen
manusc ip is based on he 18 h Decembe 2023 ial
p o ocol ( e sion 2). Rec ui men o pa icipan s s a ed
in Janua y 2024 and is es ima ed o be comple ed up o
Decembe 2025.
Abb e ia ions
BMI Body mass index
Page 8 o 9
I ia e‑Yolle e al. T ials (2024) 25:827
BP Blood p essu e
CGI-SI Clinical Global Imp ession Scale-Se e i y o Illness
CPET Ca diopulmona y exe cise es
CRF Ca dio espi a o y i ness
EqV Ven ila o y equi alen
EX Exe cise
FITT F equency, in ensi y, ime, and ype
HR Hea a e
IL In e leukin
IPAQ In e na ional Physical Ac i i y Ques ionnai e
LV-LIIT Low- olume and low-in ensi y in e al aining
MADRS Mon gome y-Asbe g Dep ession Ra ing Scale
MDD Majo dep essi e diso de
QLDS Quali y o Li e in Dep ession Scale
RMD Resis an majo dep ession
SDS Sheehan Disabili y Scale
SF-36 Sho Fo m-36 Heal h Su ey
TAU T ea men as usual
VCO2 Ca bon dioxide p oduc ion
VO2peak Peak oxygen up ake
VT Ven ila o y h eshold
Supplemen a y In o ma ion
The online e sion con ains supplemen a y ma e ial a ailable a h ps:// doi.
o g/ 10. 1186/ s13063- 024- 08685-7.
Addi ional ile 1. Resis ance aining p og am.
Addi ional ile 2. SPIRIT Checklis .
Acknowledgemen s
Thanks o he Men al Heal h Ne wo k o A aba o he commi men o his
p ojec , and he GIKAFIT esea ch g oup a he Uni e si y o he Basque Coun-
y (UPV/EHU). Likewise, hanks o BIOARABA Heal h Resea ch Ins i u e o all
he me hodological suppo and Vi o ia-Gas eiz Ci y Council o ans e ing
he acili ies o he physical ac i i y o he heal h esea ch cen e.
T ial sponso
Osakide za Basque Heal h Se ice. A aba Men al Heal h Ne wo k, Psychia ic
Hospi al o Ala a, Vi o ia-Gas eiz, Spain. A aba Kalea, 43, 01007 Vi o ia-Gas eiz,
A aba/Ála a, Basque Coun y, Spain.
Role o sponso
Rec ui men , managemen , and in e p e a ion o da a.
Role o unde s
Only inancial suppo .
Responsibili ies
The s udy will be conduc ed by he Psychia ic Hospi al o Ála a in collabo a-
ion wi h he Uni e si y o he Basque Coun y (UPV/EHU). The hospi al has
a eam o psychia y specialis s esponsible o ec ui men and signing he
in o med consen o m. They, oge he wi h he hospi al’s nu sing se ices, will
ca y ou he ques ionnai es ela ed o he s udy. The UPV/EHU esea che s
will be esponsible o he physical and physiological assessmen be o e and
a e he in e en ion and he exe cise p og amme (design and supe ision).
Bo h g oups (hospi al and uni e si y) will mee e e y h ee mon hs o iden i y
possible e o s and e alua e he s udy’s p og ess.
Au ho s’ con ibu ions
All au ho s ead and app o ed he inal manusc ip . Concep ion o he p ojec
(NIY, JEO, CPN, MTE, PMSG, SMM, EEZ). Design o he wo k and me hodology
(NIY, JEO, CPN, MTE, PMSG, SMM, ABYE, EEZ).
Funding
This p ojec is unded by he “III Con oca o ia In amu al de la Fundación Vi al
Fundazioa – IIS BIOARABA” and he Men al Heal h Ne wo k o Ála a.
Da a a ailabili y
The da a will be a ailable om he co esponding au ho upon easonable
eques .
Decla a ions
E hics app o al and consen o pa icipa e
The design o he s udy con o ms o he p inciples ou lined in he Decla a ion
o Helsinki, and he p o ocol, oge he wi h he in o med consen p oce-
du es o he TRACE-RMD s udy, we e app o ed by he E hics Commi ee o
In es iga ion o he local Hospi al (11 May 2023, Ce i ica e No. 2023–008). The
p o ocol was egis e ed wi h he Uni ed S a es Na ional Lib a y o Medicine
(ClinicalT ials.go ID no. NCT05136027). Pa icipan s will be ully in o med
o he aims and p ocedu es o he esea ch be o e collec ing hei in o med
consen and be o e he clinical and physiological examina ion. Each pa ici-
pan will be allowed o ask ques ions abou he in es iga ion. No iden i ying
images o o he pe sonal o clinical de ails o pa icipan s will be p esen ed in
epo s o he ial esul s. The pa icipan in o ma ion ma e ials and in o med
consen o ms a e a ailable om he co esponding au ho on eques .
Consen o publica ion
No applicable.
Compe ing in e es
The au ho s decla e ha hey ha e no compe ing in e es s.
Au ho de ails
1 Osakide za Basque Heal h Se ice, A aba Men al Heal h Ne wo k, Psychia ic
Hospi al o Ala a, Vi o ia-Gas eiz, Spain. 2 Bioa aba, New The apies in Men-
al Heal h G oup, Vi o ia-Gas eiz, Spain. 3 Depa men o Medicine, Facul y
o Heal h Sciences, Uni e si y o Deus o, Bilbao, Spain. 4 Depa men o Physi-
cal Educa ion and Spo , Facul y o Educa ion and Spo -Physical Ac i i y
and Spo Sciences Sec ion, GIza ea, Ki ola e a A ike a Fisikoa Ike kun za
Taldea (GIKAFIT), Socie y, Spo s, and Exe cise Resea ch G oup, Uni e si y
o he Basque Coun y (UPV/EHU), Vi o ia-Gas eiz, A aba/Ála a, Basque
Coun y, Spain. 5 Bioa aba Heal h Resea ch Ins i u e, Physical Ac i i y, Exe cise,
and Heal h g oup, Vi o ia-Gas eiz, Basque Coun y, Spain. 6 Osakide za Basque
Heal h Se ice, Bizkaia Men al Heal h Ne wo k, Hospi al o Zamudio, Bilbao,
Spain.
Recei ed: 24 Augus 2024 Accep ed: 6 Decembe 2024
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Publishe ’s No e
Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in pub-
lished maps and ins i u ional a ilia ions.