Delayed effects of tDCS combined with cognitive behavioral therapy in major depression: a randomized, double-blind pilot trial

Academic Edi o : Xiaochu Zhang
Recei ed: 4 Ap il 2025
Re ised: 18 Ap il 2025
Accep ed: 22 Ap il 2025
Published: 25 Ap il 2025
Ci a ion: Ca alho, S.; Coelho, C.G.;
Lei e, J. Delayed E ec s o DCS
Combined wi h Cogni i e Beha io al
The apy in Majo Dep ession: A
Randomized, Double-Blind Pilo T ial.
B ain Sci. 2025,15, 444. h ps://
doi.o g/10.3390/b ainsci15050444
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A icle
Delayed E ec s o DCS Combined wi h Cogni i e Beha io al
The apy in Majo Dep ession: A Randomized, Double-Blind
Pilo T ial
Sand a Ca alho 1,* , Ca a ina Gomes Coelho 1and Jo ge Lei e 2
1Psychological Neu oscience Labo a o y, Cen o de In es igação em Psicologia (CIPsi), Depa men o Basic
Psychology, School o Psychology, Uni e si y o Minho, 4710-057 B aga, Po ugal; [email p o ec ed]
2CINTESIS@RISE, CINTESIS.UPT, Po ucalense Uni e si y, 4200-072 Po o, Po ugal; [email p o ec ed]
*Co espondence: sand a [email p o ec ed]
Abs ac : Aims: This pilo s udy assessed he po en ial psychosocial and he apeu ic
impac s o augmen ing ansc anial di ec cu en s imula ion ( DCS) wi h cogni i e beha -
io al he apy (CBT) in ea men -naï e pa ien s diagnosed wi h majo dep essi e diso de
(MDD). Me hods: In his double-blind andomized con olled ial, 10 subjec s we e an-
domized in o wo g oups—CBT wi h ac i e DCS (ac i e DCS; n= 6; M = 33.3 yea s;
4 emales
) o CBT wi h sham DCS (Sham; n= 4; M = 31.2 yea s; 2 emales). Se e i y o
dep ession was measu ed wi h he Mon gome y–Åsbe g Dep ession Ra ing Scale (MADRS)
and he Beck Dep ession In en o y (BDI). Pa icipan s’ seconda y ou comes included li e
sa is ac ion, sleep quali y, and anxie y symp oms. They we e assessed a baseline, ol-
lowing ea men (week 6), and a 2, 4, 8, and 12-week ollow-ups. Resul s: By week 12,
he ac i e DCS g oup’s BDI sco es showed g ea e imp o emen ela i e o he sham
g oup. The e we e also signi ican di e ences be ween g oups o e ime in MADRS sco es.
Sleep quali y also imp o ed in he ac i e DCS g oup, wi h many pa icipan s achie ing
symp om- ee s a us—de ined as BDI sco es o 9 o less and suppo ed by consis en ly
low MADRS sco es—by he end o he ollow-up pe iod. Conclusions: These p elimina y
da a indica e ha he combina ion o DCS wi h CBT may op imize he ea men o MDD
h ough dep essi e symp om elie and imp o ed sleep, while also p olonging he bene i s
o ea men .
Keywo ds: majo dep essi e diso de ; CBT; DCS; neu omodula ion; psychia ic symp oms;
psycho he apy
1. In oduc ion
Majo dep essi e diso de (MDD) is a common and disabling mood diso de ha
a ec s no only indi idual well-being bu also social and occupa ional unc ioning. Relapse
a es o 50% o 85% [
1
] highligh he hea y bu den ha MDD places on indi iduals and
heal hca e sys ems, unde sco ing he need o e ec i e long- e m managemen s a egies.
Beyond i s emo ional and psychological oll, MDD is a majo con ibu o o mo bidi y and
mo ali y, inc easing he isk o suicide and a ange o como bid medical condi ions [
2
].
Indi iduals wi h MDD o en expe ience se e e unc ional impai men s, nega i ely a ec -
ing in e pe sonal ela ionships and o e all quali y o li e. Dep ession is also linked o
ca dio ascula , me abolic, endoc ine, and subs ance use diso de s, all o which inc ease
mo ali y isk and educe li e expec ancy. In pa icula , dep ession is ecognized as an
independen isk ac o o co ona y hea disease (CHD). S udies indica e ha indi iduals
B ain Sci. 2025,15, 444 h ps://doi.o g/10.3390/b ainsci15050444
B ain Sci. 2025,15, 444 2 o 18
wi h dep ession a e a a signi ican ly highe isk o de eloping CHD, wi h anxie y and
dep ession p e alence a es o 21% and 13%, espec i ely, in CHD pa ien s [
3
]. The complex
in e play be ween MDD and hese medical como bidi ies highligh s he u gen need o
in eg a ed ea men app oaches ha add ess bo h men al and physical heal h o imp o e
o e all pa ien ou comes.
Recen e idence unde sco es he global bu den o men al diso de s among child en
and adolescen s, emphasizing he ea ly onse and pe sis ence o hese condi ions. A com-
p ehensi e analysis based on Global Bu den o Disease (GBD) 2019 da a [
4
] es ima es
ha app oxima ely 293 million indi iduals aged 5 o 24 yea s— ep esen ing 11.63% o
his popula ion—expe ience a leas one men al diso de . The p e alence ises wi h age,
inc easing om 6.80% in child en (5–9 yea s) o 12.40% in ea ly adolescence (10–14 yea s),
13.96% in mid-adolescence (15–19 yea s), and 13.63% in young adul hood (20–24 yea s).
These esul s unde sco e he u gen need o ea ly in e en ions o p e en las ing psy-
chological and unc ional impai men s. Gi en he high p e alence o dep ession wi hin
his demog aphic, de eloping inno a i e, scalable, and accessible he apeu ic app oaches
emains a p essing global men al heal h p io i y.
Despi e ex ensi e esea ch and ea men op ions, esponse a es o MDD emain
unsa is ac o y. Al hough pha maco he apy and cogni i e beha io al he apy (CBT) a e
conside ed i s -line ea men s, ecen e idence sugges s hei e ec i eness may be o e -
es ima ed due o ac o s like publica ion bias and esea che allegiance. Fo ins ance,
s udies ha e ound ha he e icacy o psychological in e en ions o dep ession has been
o e es ima ed in he published li e a u e, jus as i has been o pha maco he apy [
5
]. Addi-
ionally, esea che allegiance has been iden i ied as a po en ial sou ce o bias in andomized
clinical ials o psychological in e en ions [
6
]. Mo eo e , head- o-head compa isons o
psycho he apies e sus pha maco he apies e eal negligible di e ences, while combined
ea men o e s only a modes bene i o e mono he apy [
7
]. These indings highligh he
u gen need o no el o adjunc i e he apeu ic s a egies o enhance ea men ou comes.
One p omising al e na i e in e en ion is ansc anial di ec cu en s imula ion
( DCS). DCS is a non-in asi e b ain s imula ion echnique ha modula es co ical ex-
ci abili y and has shown p omise in alle ia ing dep essi e symp oms, cu en ly holidng
a le el o e idence A [
8
]. G owing e idence om andomized con olled ials and me a-
analyses sugges s ha DCS may se e as an e ec i e adjunc o con en ional ea men s
o MDD. Me a-analyses ha e u he co obo a ed he e icacy o DCS in ea ing de-
p ession. A e iew o se e al andomized ials ound ha DCS signi ican ly educes
dep essi e symp oms, especially when deli e ed a 2 mA o 30 min sessions [
9
]. Ad-
di ionally, DCS has demons a ed he po en ial o educe suicidal idea ion and p o ide
sus ained an idep essan e ec s [
10
]. S udies ha e shown ha a ge ing he le DLPFC can
signi ican ly imp o e dep essi e symp oms o a mon h o longe , indica ing he du abili y
o DCS bene i s. These indings posi ion DCS as a p omising al e na i e o adjunc i e
in e en ion o MDD, pa icula ly o pa ien s who ha e no esponded adequa ely o
adi ional he apies.
One o he key neu obiological a ionales o using DCS in MDD is based on elec o-
physiological e idence o on al alpha asymme y obse ed in es ing elec oencephalo-
g am (EEG) eco dings. Indi iduals wi h MDD o en exhibi educed ac i i y in he le
do sola e al p e on al co ex (DLPFC) ela i e o he igh , a pa e n associa ed wi h emo-
ional dys egula ion and dep essi e symp oma ology [
11
]. This asymme y may inc ease
ulne abili y o dep ession, wi h le DLPFC ac i i y linked o app oach mo i a ion and
igh DLPFC ac i i y o wi hd awal and a oidance [
12
]. Recen esea ch has examined he
co ela ion be ween on al alpha asymme y (FAA) and MDD. A 2023 me a-analysis o
23 s udies (1928 MDD pa ien s, 2604 con ols) assessed on al alpha asymme y (FAA)
B ain Sci. 2025,15, 444 3 o 18
as a possible bioma ke o MDD. The esea ch showed ha indi iduals wi h MDD dis-
played inc eased igh on al EEG alpha asymme y ela i e o non-dep essed indi iduals,
indica ing ha on al alpha asymme y may unc ion as a bioma ke o MDD [
13
]. The
indings co obo a e he idea ha diminished ac i i y in he le do sola e al p e on al
co ex (DLPFC) compa ed o he igh is linked o emo ional dys egula ion and dep essi e
symp oms. This imbalance may p edispose indi iduals o dep ession, as heigh ened le
DLPFC ac i a ion coincides wi h app oach desi e, whe eas inc eased igh DLPFC ac i i y
is linked o wi hd awal and a oidance endencies.
By deli e ing a low-in ensi y di ec cu en ( ypically 1–2.5 mA) h ough scalp elec-
odes o 10–30 min, DCS can depola ize o hype pola ize neu onal memb anes, e ec-
i ely modula ing co ical exci abili y [
14
]. The mos common elec ode mon age in ol es
placing he anode (exci a o y) o e he le DLPFC and he ca hode (inhibi o y) o e he
igh DLPFC o posi ioning he anode o e he le DLPFC and he ca hode o e he igh
sup ao bi al egion, he e o e es o ing he in e -hemisphe ic imbalance [
15
]. Al hough
DCS has p o en e ec i e in educing MDD symp oms, i s po en ial as an adjunc o
psycho he apy emains unde explo ed. Because bo h CBT and DCS in luence p e on al
egula ion o emo ion and cogni ion, combining hem has a s ong heo e ical ounda ion
o enhancing ea men ou comes. A s udy p o ocol by Ca alho e al. (2020) [
15
] p oposed
in es iga ing he clinical and mechanis ic e ec s o combining CBT and DCS in MDD
ea men . Building on his ounda ion, he p esen s udy aims o in es iga e he epe i i e
e ec s o DCS combined wi h indi idualized CBT in alle ia ing dep essi e symp oms
in indi iduals wi h mild o mode a e MDD who a e CBT-naï e. We hypo hesize ha
combining DCS wi h CBT will ha e a syne gis ic e ec , imp o ing CBT’s e ec i eness and
esul ing in be e clinical ou comes han CBT alone. Addi ionally, we aim o examine he
long- e m e ec s o hese in e en ions, assessing hei sus ained impac o e a h ee-mon h
ollow-up pe iod.
Taken oge he , hese indings highligh he necessi y o comp ehensi e, e idence-
in o med he apy app oaches ha a ge bo h he neu obiological and psychosocial oun-
da ions o dep ession. This s udy aimed o assess he possible syne gis ic bene i s o
combining DCS and CBT, bo h o which a ge p e on al co ex unc ion, in pa ien s
wi h mild o se e e, ea men -naï e MDD. We p opose ha including ac i e DCS in o
pe sonalized CBT will esul in mo e signi ican educ ions in dep essi e symp oms, as
well as enhancemen s in sleep, anxie y, and li e sa is ac ion, in con as o CBT combined
wi h sham s imula ion. Mo eo e , we an icipa e ha he he apeu ic e ec s would endu e
and e en in ensi y du ing a 12-week ollow-up pe iod. This pilo ial seeks o u nish
ini ial in o ma ion abou he e icacy and longe i y o his combina ion in e en ion and o
guide he o mula ion o mo e e ec i e and scalable ea men models o MDD.
2. Ma e ials and Me hods
2.1. E hical App o al and S udy Regis a ion
This s udy was conduc ed in acco dance wi h he la es e ision o he Decla a ion
o Helsinki and ecei ed e hical app o al om he Subcommi ee on E hics o Li e and
Heal h Sciences (SECVS) a he Uni e si y o Minho (App o al No. SECVS 174/2017). All
pa icipan s p o ided w i en in o med consen p io o en ollmen . The s udy p o ocol
was egis e ed wi h he Uni ed S a es Na ional Lib a y o Medicine Clinical T ials Reg-
is y (ClinicalT ials.go ID: NCT03548545) on 7 June 2018 (P o ocol Ve sion 1). Fu he
me hodological de ails a e a ailable in he published p o ocol by Ca alho e al. (2020) [
15
]:
clinical ials.go /c 2/show/NCT03548545 (accessed on 25 Ap il 2023).
B ain Sci. 2025,15, 444 4 o 18
2.2. Pa icipan Rec ui men and Eligibili y C i e ia
Pa icipan s we e ec ui ed h ough mul iple sou ces, including social media ad e -
isemen s, lye s dis ibu ed h oughou he ci y o B aga, and ins i u ional mailing lis s
om he Uni e si y o Minho. Eligibili y was es ic ed o indi iduals expe iencing an
acu e majo dep essi e episode who me he Diagnos ic and S a is ical Manual o Men al
Diso de s (DSM-5) c i e ia o MDD. To ensu e a well-cha ac e ized sample, he ollowing
inclusion c i e ia we e applied: pa icipan s had o be be ween 18 and 75 yea s o age,
p esen a diagnosis o unipola , non-psycho ic MDD, and sco e
≥
7 on he Mon gome y-
Åsbe g Dep ession Ra ing Scale (MADRS) and
≥
10 on he Beck Dep ession In en o y (BDI).
Addi ionally, all pa icipan s we e equi ed o demons a e low suicide isk, which was
assessed using he S uc u ed Clinical In e iew o DSM (SCID). Al hough he SCID-5
e sion was no ye a ailable o ou eam a he ime o da a collec ion, he s uc u ed
in e iew was conduc ed by a ained clinician, and all diagnoses and isk assessmen s
we e con i med acco ding o DSM-5 c i e ia. As a supplemen a y measu e, suicide isk
was also e alua ed using I em 9 o he BDI, which speci ically add esses suicidal hough s.
Exclusion c i e ia encompassed any con aindica ions o ansc anial di ec cu en s im-
ula ion ( DCS), such as he p esence o me al implan s in he head o implan ed c anial
medical de ices. Pa icipan s we e also excluded i hey p esen ed wi h any signi ican o
uns able neu ological o psychia ic condi ions o he han MDD, including bu no limi ed
o epilepsy, Pa kinson’s disease, demen ia, ea ing diso de s, o obsessi e-compulsi e spec-
um diso de s. Addi ional exclusion c i e ia included a li e ime his o y o subs ance use
diso de s, a diagnosis o a pe sonali y diso de , o any se e e medical condi ion likely o
impai unc ional s a us du ing he s udy pe iod (e.g., ac i e cance o se ious ca diac, enal,
o hepa ic condi ions). Al hough he o iginal s udy p o ocol excluded indi iduals ecei ing
psychopha macological ea men , an amendmen was implemen ed o include pa icipan s
unde going s able pha maco he apy. This adjus men was made o enhance he ex e nal
alidi y and clinical ele ance o he indings, while main aining
me hodological in eg i y.
2.3. S udy Design
This andomized, double-blind, con olled pilo ial was designed o assess he
he apeu ic e icacy o combining DCS wi h CBT in adul s expe iencing an acu e episode o
MDD. The in e en ion spanned a o al du a ion o six weeks. Pa icipan s we e andomly
alloca ed o one o wo condi ions: ac i e DCS pai ed wi h CBT o sham DCS pai ed wi h
CBT. Each pa icipan comple ed 18 sessions o DCS (ac i e o sham) and 12 sessions o
CBT, implemen ed in acco dance wi h a s anda dized ea men p o ocol (Figu e 1).
The in e en ion was s uc u ed in o wo consecu i e phases. The acu e ea men
phase, co esponding o he i s wo weeks, consis ed o 10 consecu i e weekday sessions
o DCS (Monday o F iday). Du ing his pe iod, no CBT sessions we e adminis e ed.
The ein o cemen phase, co e ing weeks h ee o six, inco po a ed wo weekly DCS
sessions (on Mondays and F idays), each las ing 30 min. CBT was in oduced du ing his
phase, wi h pa icipan s a ending a o al o ou indi idual he apy sessions deli e ed by
a licensed clinical psychologis . Clinical assessmen s we e conduc ed a se en key ime
poin s: baseline (p io o andomiza ion), end o he acu e phase (week 2), end o he
ein o cemen phase (week 6), and a ou pos -in e en ion ollow-up in e als (2, 4, 8,
and 12 weeks). This schedule allowed o he e alua ion o bo h immedia e and sus ained
ea men e ec s. All s udy p ocedu es—including clinical e alua ions, neu omodula ion
sessions, and psycho he apy—we e ca ied ou a he Clinical Se ice o he School o
Psychology, Uni e si y o Minho. Pa icipan s we e e e ed by P ima y Ca e Physicians,
ensu ing a clinically ep esen a i e coho o indi iduals ac i ely seeking ea men o
dep essi e symp oms.
B ain Sci. 2025,15, 444 5 o 18
B ainSci.2025,15,xFORPEERREVIEW5o 20
Figu e1.S udydesignandassessmen  imelineo  he wo-a m andomizedcon olled ial(RCT),
compa ingac i e s.sham ansc anialdi ec cu en s imula ion( DCS),combinedwi hcogni i e
beha io al he apy(CBT).
Thein e en ionwass uc u edin o woconsecu i ephases.Theacu e ea men 
phase,co esponding o he i s  woweeks,consis edo 10consecu i eweekdaysessions
o  DCS(Monday oF iday).Du ing hispe iod,noCBTsessionswe eadminis e ed.The
ein o cemen phase,co e ingweeks h ee osix,inco po a ed woweekly DCSsessions
(onMondaysandF idays),eachlas ing30min.CBTwasin oduceddu ing hisphase,
wi hpa icipan sa endinga o alo  ou indi idual he apysessionsdeli e edbya
licensedclinicalpsychologis .Clinicalassessmen swe econduc eda se enkey ime
poin s:baseline(p io  o andomiza ion),endo  heacu ephase(week2),endo  he
ein o cemen phase(week6),anda  ou pos -in e en ion ollow-upin e als(2,4,8,
and12weeks).Thisscheduleallowed o  hee alua iono bo himmedia eandsus ained
ea men effec s.Alls udyp ocedu es—includingclinicale alua ions,neu omodula ion
sessions,andpsycho he apy—we eca iedou a  heClinicalSe iceo  heSchoolo 
Psychology,Uni e si yo Minho.Pa icipan swe e e e edbyP ima yCa ePhysicians,
ensu ingaclinically ep esen a i ecoho o indi idualsac i elyseeking ea men  o 
dep essi esymp oms.
2.4.Randomiza ionandBlindingP ocedu es
Randomiza ionp ocedu es ollowed hep o ocolou linedbyCa alhoe al.(2020)
[15].A e con i mingeligibili yandob ainingw i enin o medconsen ,pa icipan s
we e andomlyassigned ooneo  woin e en iona ms—ac i e DCScombinedwi h
CBTo sham DCScombinedwi hCBT—usingacompu e -gene a ed,web-based
andomiza ionsys em.A1:1alloca ion a iowasapplied oensu ebalancedg oup
dis ibu ion.Top ese ealloca ionconcealmen andensu eme hodological igo , he
andomiza ionsequencewass o edinsealed,opaqueen elopesandaccessedonlya  he
imeo assignmen .Blindingwasmain ainedac ossmul iplele elso  hes udy;
pa icipan s,CBT he apis s,clinicalassesso s,andda aanalys swe eallblinded og oup
alloca ion h oughou  he ial.Due o he echnical equi emen so s imula iondeli e y,
he esea chs aff esponsible o adminis e ing DCSwe eno blinded,as heywe e
equi ed oimplemen speci ics imula ionpa ame e s.Nose iousad e see en swe e
obse eddu ing hecou seo  hes udy.In hee en o anad e see en  equi ing
unblinding, heP incipalIn es iga o wasau ho ized odisclose hepa icipan ’sg oup
alloca ionand epo  heinciden  o heE hicsCommi eewi hin24h,inacco dancewi h
ins i u ionalande hicalsa e yp o ocols.
Figu e 1. S udy design and assessmen imeline o he wo-a m andomized con olled ial (RCT),
compa ing ac i e s. sham ansc anial di ec cu en s imula ion ( DCS), combined wi h cogni i e
beha io al he apy (CBT).
2.4. Randomiza ion and Blinding P ocedu es
Randomiza ion p ocedu es ollowed he p o ocol ou lined by Ca alho e al. (2020) [
15
].
A e con i ming eligibili y and ob aining w i en in o med consen , pa icipan s we e an-
domly assigned o one o wo in e en ion a ms—ac i e DCS combined wi h CBT o sham
DCS combined wi h CBT—using a compu e -gene a ed, web-based andomiza ion sys em.
A 1:1 alloca ion a io was applied o ensu e balanced g oup dis ibu ion. To p ese e
alloca ion concealmen and ensu e me hodological igo , he andomiza ion sequence was
s o ed in sealed, opaque en elopes and accessed only a he ime o assignmen . Blinding
was main ained ac oss mul iple le els o he s udy; pa icipan s, CBT he apis s, clinical
assesso s, and da a analys s we e all blinded o g oup alloca ion h oughou he ial.
Due o he echnical equi emen s o s imula ion deli e y, he esea ch s a esponsible
o adminis e ing DCS we e no blinded, as hey we e equi ed o implemen speci ic
s imula ion pa ame e s. No se ious ad e se e en s we e obse ed du ing he cou se o he
s udy. In he e en o an ad e se e en equi ing unblinding, he P incipal In es iga o
was au ho ized o disclose he pa icipan ’s g oup alloca ion and epo he inciden o he
E hics Commi ee wi hin 24 h, in acco dance wi h ins i u ional and e hical sa e y p o ocols.
2.5. Sc eening and Baseline Assessmen
Indi iduals who exp essed in e es in pa icipa ing we e ini ially sc eened h ough
a s uc u ed in ake p ocess o e alua e eligibili y o s udy inclusion. Du ing his ini ial
con ac , a s anda dized ques ionnai e was adminis e ed o assess compliance wi h he
inclusion and exclusion c i e ia, as well as sui abili y o ansc anial di ec cu en s imula-
ion ( DCS) and elec oencephalog am (EEG) p ocedu es. Po en ial pa icipan s we e ully
in o med o he s udy’s aims, p ocedu es, and po en ial isks, and had he oppo uni y o
ask ques ions p io o p o iding w i en in o med consen . Eligible pa icipan s we e hen
scheduled o he baseline assessmen (T0). Du ing his session, pa icipan s comple ed
s anda dized demog aphic and medical his o y ques ionnai es, ollowed by adminis a ion
o he p ima y clinical ou come measu es: he Mon gome y-Åsbe g Dep ession Ra ing
Scale (MADRS) and he Beck Dep ession In en o y (BDI). Indi iduals who me he eligi-
bili y c i e ia based on hese assessmen s p oceeded o comple e he seconda y ou come
measu es, including he Beck Anxie y In en o y (BAI), S a e-T ai Anxie y In en o y (STAI-
Y), Pi sbu gh Sleep Quali y Index (PSQI), and he Sa is ac ion wi h Li e Scale (SWLS).
To con i m he p esence o MDD acco ding o DSM-5 c i e ia, pa icipan s unde wen a

B ain Sci. 2025,15, 444 6 o 18
S uc u ed Clinical In e iew o DSM-5 (SCID-5), conduc ed by a ained clinician. The
en i e baseline assessmen p o ocol equi ed app oxima ely wo hou s o comple e.
2.6. In e en ion Phases and Follow-Up Assessmen s
Following he baseline assessmen (T0), pa icipan s en e ed he acu e ea men phase,
which spanned wo weeks. Du ing his phase, indi iduals ecei ed 10 consecu i e weekday
sessions o ansc anial di ec cu en s imula ion ( DCS), adminis e ed Monday h ough
F iday. Each session consis ed o ei he ac i e o sham s imula ion a 2 mA o 30 min. In
pa allel, pa icipan s began cogni i e beha io al he apy (CBT), a ending wo sessions
pe week (Monday and F iday), o aling ou sessions du ing his ini ial phase. A he
end o he acu e ea men phase (T1; week 2), pa icipan s unde wen a comp ehensi e
eassessmen ha included he same ba e y o p ima y and seconda y clinical ou come
measu es adminis e ed a baseline. Pa icipan s hen ansi ioned in o he ein o cemen
phase, which co e ed weeks 3 o 6. Du ing his pe iod, hey con inued o ecei e wo
DCS sessions pe week (30 min each, on Mondays and F idays), alongside CBT sessions a
he same equency. Upon comple ing his phase (T2; week 6), pa icipan s unde wen a
pos - ea men e alua ion, using he same clinical ou come measu es. In addi ion o clinical
assessmen s, h ee-minu e es ing-s a e EEG eco dings we e ob ained a T0, T1, and T2. As
EEG analyses all ou side he scope o he p esen manusc ip , hose da a will be epo ed
in a sepa a e publica ion. To e alua e he du abili y o ea men e ec s, pa icipan s we e
u he assessed a ou ollow-up ime poin s: a 2 weeks (T3), 4 weeks (T4), 8 weeks (T5),
and 12 weeks (T6) a e he conclusion o he in e en ion. This ollow-up pe iod enabled a
longi udinal e alua ion o symp om ajec o ies and main enance o he apeu ic ou comes.
2.7. Cogni i e Beha io al The apy (CBT) P o ocol
The cogni i e beha io al he apy (CBT) componen o he in e en ion was s uc-
u ed in acco dance wi h Aa on T. Beck’s cogni i e heo y o dep ession and deli e ed
ollowing e idence-based clinical guidelines. Each session las ed app oxima ely 60 min
and was conduc ed indi idually o allow o pe sonalized he apeu ic engagemen . The
in e en ion was ailo ed o he se e i y and speci ic symp om p o ile o each pa icipan ,
wi h an emphasis on iden i ying, e alua ing, and es uc u ing maladap i e cogni i e
pa e ns, dys unc ional belie s, and associa ed beha io al esponses con ibu ing o dep es-
si e symp oma ology. The apeu ic s a egies included cogni i e es uc u ing, beha io al
ac i a ion, hough moni o ing, and emo ion egula ion echniques. Sessions also inco po-
a ed psychoeduca ion ega ding he cogni i e model o dep ession and elapse p e en ion
s a egies in la e phases o ea men . The he apeu ic p ocess was designed o enhance
pa icipan s’ coping skills, p omo e insigh in o nega i e au oma ic hough s, and os e he
de elopmen o adap i e p oblem-sol ing app oaches. All CBT sessions we e deli e ed
by a licensed clinical psychologis egis e ed wi h he O dem dos Psicólogos Po ugueses
(OPP— he o icial egula o y body o he psychology p o ession in Po ugal), wi h o mal
aining in cogni i e beha io al he apy. To ensu e consis ency, ideli y o he ea men
model, and adhe ence o p o ocol guidelines, weekly supe ision mee ings we e held
be ween he ea ing psychologis and a senio clinical supe iso (SC), who possessed
ex ensi e clinical expe ience in CBT o mood diso de s. Supe ision ocused on case con-
cep ualiza ion, ea men planning, session con en , and add essing he apeu ic challenges,
he eby ensu ing he quali y and in eg i y o he in e en ion ac oss pa icipan s.
2.8. T ansc anial Di ec Cu en S imula ion ( DCS) Adminis a ion
T ansc anial di ec cu en s imula ion ( DCS) was adminis e ed using he Eldi h DC
S imula o Plus (Neu oConn GmbH, Ilmenau, Ge many), a CE-ce i ied de ice widely
employed in clinical and expe imen al neu omodula ion esea ch. S imula ion was de-
B ain Sci. 2025,15, 444 7 o 18
li e ed h ough wo saline-soaked sponge elec odes (25 cm
2
each), secu ed using elas ic
headbands o ensu e consis en placemen and con ac . Elec ode mon age ollowed he
in e na ional 10–20 EEG sys em: he anodal elec ode was posi ioned o e he le do sola -
e al p e on al co ex (DLPFC), a si e F3, and he ca hodal elec ode o e he igh DLPFC,
a si e F4. This bila e al on al con igu a ion is suppo ed by neu ophysiological e idence
linking p e on al asymme y o a ec i e egula ion and has been equen ly used in s ud-
ies a ge ing dep essi e symp oms. In he ac i e DCS condi ion, pa icipan s ecei ed a
cons an cu en o 2 mA ( esul ing in a cu en densi y o 0.80 A/m
2
) o a o al du a ion o
30 min. S imula ion included a 15 s amp-up and amp-down o minimize discom o and
p e en sudden pe cep ual sensa ions associa ed wi h ab up cu en onse o o se . In he
sham condi ion, he elec ode mon age and amp-up/down pa ame e s we e iden ical o
hose o he ac i e condi ion; howe e , he de ice au oma ically discon inued s imula ion
a e 15 s o 2 mA cu en . This b ie s imula ion pe iod is conside ed su icien o mimic he
ini ial ingling sensa ion expe ienced in ac i e s imula ion, he eby p ese ing he in eg i y
o he blinding p o ocol. Each DCS session las ed app oxima ely 40 min, accoun ing o
p epa a ion, elec ode placemen , and s imula ion ime. All sessions we e conduc ed in
a quie , con olled en i onmen , wi h pa icipan s sea ed com o ably in a semi- eclined
posi ion o minimize mo emen and ensu e op imal elec ode con ac . Impo an ly, DCS
was adminis e ed by a ained esea ch assis an who was no in ol ed in any aspec o
clinical assessmen o cogni i e beha io al he apy deli e y. This p ocedu al sepa a ion
was implemen ed o p ese e he double-blind design, ensu ing ha he apis s, assesso s,
and pa icipan s emained blinded o he s imula ion condi ion h oughou he s udy.
2.9. S a is ical Analysis
Gi en he small sample size and he non-no mal dis ibu ion o he da a in his pilo
s udy, only non-pa ame ic s a is ical analyses we e pe o med. To explo e po en ial g oup
di e ences in sociodemog aphic cha ac e is ics be ween he ac i e and sham DCS g oups,
Chi-squa ed es s we e used o ca ego ical a iables, while he Mann–Whi ney U es
was applied o con inuous a iable. G oup di e ences in psychia ic symp oms ac oss he
se en assessmen ime poin s we e analyzed using he Mann–Whi ney U es , wi h e ec
sizes calcula ed using he ank-bise ial co ela ion.
Addi ionally, a seconda y analysis was conduc ed o explo e symp om imp o emen
o e ime o each g oup ela i e o baseline. We calcula ed g oup-no malized change
sco es; each pa icipan ’s symp om sco es a ime poin s T1 o T6 we e di ided by he a e -
age symp om sco e o hei espec i e g oup a T0. This app oach allowed us o examine
wi hin-g oup imp o emen pa e ns and be ween-g oup di e ences while accoun ing o
ini ial baseline a iabili y. The Mann–Whi ney U es was used o g oup compa isons,
wi h e ec sizes calcula ed using he ank-bise ial co ela ion ( ).
To supplemen con inuous ou come analyses, we also compu ed clinically meaning ul
ca ego ical ou comes. Fo he MADRS, a educ ion o
≥
12 poin s om baseline was de ined
as a clinically meaning ul ea men esponse, in line wi h es ablished guidelines [
13
]. Fo
he BDI, a sco e o
≤
9 was used as a cu o o de ine emission, based on p io alida ion
s udies [
16
]. Pa icipan s we e ca ego ized acco dingly (Yes/No), and di e ences be ween
g oups a each ime poin we e es ed using Chi-squa ed es s. This app oach enabled an
e alua ion o bo h symp om ajec o ies and clinically ele an ea men miles ones.
Bi a ia e co ela ions be ween symp oms we e analyzed a each assessmen ime using
Spea man’s co ela ion coe icien . Desc ip i e s a is ics, g oup di e ences, and co ela ion
analyses we e ca ied ou using IBM SPSS S a is ics 23. Addi ionally, all esul g aphs and
e ec size calcula ions we e pe o med using R so wa e, e sion V 4.4.2.
B ain Sci. 2025,15, 444 8 o 18
3. Resul s
3.1. Sociodemog aphic Da a
The e o e, om he 13 (n= 13) pa icipan s who we e ini ially sc eened, 1 pa icipan
was excluded due o egula subs ance use, 1 pa icipan was excluded due o he addi ional
diagnosis o Tou e e synd ome, and 1 pa icipan was excluded because hey s a ed aking
psychopha macological ea men wi h se aline.
Ten adul s diagnosed wi h MDD pa icipa ed in his clinical ial (age: Mdn = 31,
IQR = 20.5
; 60% emale). Pa icipan s we e alloca ed in o ei he he ac i e g oup (n= 6) o
he sham g oup (n= 4). O e all, 60% o pa icipan s had comple ed high school educa ion,
80% we e single, and 50% we e employed a he ime o he i s assessmen . None o
he pa icipan s me diagnos ic c i e ia o addi ional psychia ic diso de s aside om
majo dep essi e diso de , and no psychia ic como bidi ies we e p esen a baseline. All
pa icipan s we e also sc eened o suicide isk using he S uc u ed Clinical In e iew o
DSM (SCID), which con i med low isk in all cases.
Table 1shows he sociodemog aphic cha ac e is ics o pa icipan s, compa ing bo h
he ac i e and sham g oups. All a iables p esen ed non-signi ican di e ences be ween
he wo g oups.
Table 1. Sociodemog aphic cha ac e is ics.
Ac i e G oup
(n= 6)
Sham G oup
(n= 4) U/χ2d p
n(%) n(%)
Age, Mdn [IQR] 31.00 [16.50] 31.50 [23.25] 10.00 - 0.670
Sex 0.28 1 0.598
Female 4 (66.7) 2 (50)
Male 2 (33.3) 2 (50)
Educa ion 0.63 1 0.429
High school 3 (50) 3 (75)
Highe educa ion 3 (50) 1 (25)
Ma i al s a us 2.86 2 0.240
Single 3 (50) 4 (100)
Ma ied/non-ma i al pa ne ship 1 (16.7) -
Di o ced 2 (33.3) -
Wo k s a us 1.88 2 0.392
S uden - 1 (25)
Employed 3 (50) 2 (50)
Unemployed 3 (50) 1 (25)
3.2. G oups Di e ences in Psychia ic Symp oms o e Time
Based on he analysis o di e ences be ween he ac i e and sham DCS g oups o e
ime (Figu e 2), symp om imp o emen was obse ed in bo h g oups. As expec ed, he
ac i e DCS g oup showed g ea e long- e m bene i s o mos psychological symp oms.
Al hough no signi ican di e ences we e obse ed in dep ession symp oms un il he
las ollow-up assessmen (U = 2.00, Z =
−
2.15, p< 0.05) (Figu e 2A,B), he ac i e DCS
g oup s a ed wi h highe mean sco es on bo h ins umen s. F om T2 assessmen , his
g oup p esen ed ewe symp oms compa ed o he sham g oup, showing sco es below
he cu -o s o mino dep essi e symp oms (MADRS < 6; BDI < 9). The e ec sizes also
sugges ed a s onge and mo e consis en g oup di e ence a he end o he ollow-up
pe iod in bo h ques ionnai es.
B ain Sci. 2025,15, 444 9 o 18
B ainSci.2025,15,xFORPEERREVIEW10o 20



Figu e2.Symp om ajec o iesac oss ea men and ollow-upphases o bo hg oups.Symp om
ajec o iesac ossassessmen s o  heac i e(blue)andsham(yellow)g oups.Panelsshow:(A)
MADRS,(B)BDI,(C)BAI,and(D)STAI-Ysco es omT0 oT6,(E)SleepQuali y,and(F)Li e
Sa is ac ionsco es omT0 oT6.Blacklines ep esen g oup ends.Pea son’s  aluesindica e
symp omchangeo e  ime;p<0.05isma kedwi h*.
Despi e hesmallsamplesize,wepe o med woaddi ionalanalyses(Figu e3).The
i s analysiswasbasedona12-poin  educ ionin heMADRS ombaseline,a h eshold
associa edin heli e a u ewi hsubs an ialsymp omchange[13].Da awe eca ego ized
asYeso No,andChi-squa ed es swe epe o med o each imepoin .On helas  ol-
low-up(T6), he ewasasubs an ialdiffe enceinsco esbe ween hosewho ecei ed
Figu e 2. Symp om ajec o ies ac oss ea men and ollow-up phases o bo h g oups. Symp-
om ajec o ies ac oss assessmen s o he ac i e (blue) and sham (yellow) g oups. Panels show:
(A) MADRS
, (B) BDI, (C) BAI, and (D) STAI-Y sco es om T0 o T6, (E) Sleep Quali y, and (F) Li e
Sa is ac ion sco es om T0 o T6. Black lines ep esen g oup ends. Pea son’s alues indica e
symp om change o e ime; p< 0.05 is ma ked wi h *.
Despi e no signi ican di e ences being obse ed in anxie y symp oms (Figu e 2C,D),
an in e es ing bu non-signi ican pa e n was obse ed in he STAI-Y1 (Figu e 2D), in
which he ac i e DCS g oup main ained a dec ease in symp oms ac oss all pos -baseline
assessmen poin s un il he end o he expe imen , wi h medium o la ge e ec size alues.
Al hough sleep quali y sco es we e be e in he sham DCS g oup a baseline and T1, wi h a
signi ican di e ence (U = 2.50, Z =
−
2.04, p< 0.05; U = 1.00, Z =
−
2.39, p< 0.05), he ac i e
DCS g oup showed a con inuous imp o emen in sleep quali y h oughou he expe imen ,
B ain Sci. 2025,15, 444 16 o 18
5. Conclusions
This pilo s udy sugges s ha he in eg a ion o ansc anial di ec cu en s imula ion
( DCS) and cogni i e beha io al he apy (CBT) may imp o e ea men e icacy o pa ien s
wi h MDD, especially in he long- e m elie o symp oms. While bo h g oups we e able
o eap bene i s om CBT, hose who we e gi en ac i e DCS we e able o achie e e en
g ea e and longe -las ing educ ions in dep essi e symp oms. Mos no ably, he bene i s
ex ended beyond dep ession, encompassing educed anxie y, imp o ed sleep, g ea e li e
sa is ac ion, and an enhanced sense o well-being, sugges ing ha he combined ea men
may igge a b oade and p og essi ely accele a ing he apeu ic e ec .
These indings suppo he heo y ha neu omodula ion o he do sola e al p e on al
co ex enhances neu oplas ici y and cogni i e con ol, he eby ampli ying he e ec s o
CBT. The e ec s ha we e no ed du ing ollow-up assessmen s highligh he need o
conside longe ime ames, pa icula ly in e e ence o measu ing he e ec i eness o
mul i-p onged he apy app oaches.
Despi e hese d awbacks, he conclusions d awn om he s udy add s eng h o
exis ing li e a u e while simul aneously c ea ing oppo uni ies o u he esea ch. Fu u e
ials should include mo e di e se pa icipan samples and inco po a e neu obiological
measu es—such as EEG o neu oimaging— o be e unde s and unde lying mechanisms
and e ine ea men s a egies. In u n, hese esul s could help de elop as e -ac ing,
ailo ed ea men plans o indi iduals wi h majo dep essi e diso de , especially hose
who do no espond well o adi ional ea men me hods.
Au ho Con ibu ions: Concep ualiza ion, S.C. and J.L.; me hodology, S.C.; o mal analysis, C.G.C.;
in es iga ion, S.C., J.L. and C.G.C.; da a cu a ion, C.G.C.; w i ing—o iginal d a , S.C.; w i ing—
e iew and edi ing, C.G.C. and J.L.; isualiza ion, S.C.; supe ision, S.C. and J.L.; p ojec adminis-
a ion, S.C. and J.L.; unding acquisi ion, S.C. All au ho s ha e ead and ag eed o he published
e sion o he manusc ip .
Funding: This wo k is suppo ed by he Po uguese Founda ion o Science and Technology and
he Po uguese Minis y o Science, h ough na ional unds, and co- inanced by FEDER h ough
COMPETE2020 unde he PT2020 Pa ne ship Ag eemen (POCI-01-0145-FEDER-007653) and is also
unded by he FCT g an PTDC/PSI-ESP/29701/2017. This wo k was conduc ed a he Psychology
Resea ch Cen e—CIPsi (PSI/01662), School o Psychology, Uni e si y o Minho, suppo ed by
Fundação pa a a Ciência e a Tecnologia (FCT; UID/01662/2020) h ough he Po uguese S a e Budge .
Ins i u ional Re iew Boa d S a emen : The s udy was conduc ed in acco dance wi h he Decla a ion
o Helsinki and app o ed by he Ins i u ional Re iew Boa d (Subcommi ee on E hics o Li e and
Heal h Sciences, SECVS) o he Uni e si y o Minho (p o ocol code SECVS 174/2017; app o ed on 20
Decembe 2017).
In o med Consen S a emen : In o med consen was ob ained om all subjec s in ol ed in
he s udy.
Da a A ailabili y S a emen : The da a suppo ing he indings o his s udy a e a ailable om he
co esponding au ho upon easonable eques . Due o e hical and p i acy es ic ions ela ed o
sensi i e clinical in o ma ion, he da ase is no publicly a ailable.
Acknowledgmen s: We a e deeply g a e ul o all pa icipan s who gene ously ga e hei ime and
e o o ake pa in his s udy. The au ho s would like o since ely hank all s uden s om he School
o Psychology o hei aluable assis ance wi h da a collec ion.
Con lic s o In e es : The au ho s decla e ha he esea ch was conduc ed in he absence o any
comme cial o inancial ela ionships ha could be cons ued as a po en ial con lic o in e es .

B ain Sci. 2025,15, 444 17 o 18
Abb e ia ions
The ollowing abb e ia ions a e used in his manusc ip :
Abb e ia ion De ini ion
MDD majo dep essi e diso de
CBT cogni i e beha io al he apy
DCS ansc anial di ec cu en s imula ion
DLPFC do sola e al p e on al co ex
MADRS Mon gome y–Åsbe g Dep ession Ra ing Scale
BDI Beck Dep ession In en o y
BAI Beck Anxie y In en o y
STAI S a e-T ai Anxie y In en o y
PSQI Pi sbu gh Sleep Quali y Index
SWLS Sa is ac ion Wi h Li e Scale
EEG elec oencephalog am
SCID-5 S uc u ed Clinical In e iew o DSM-5
SECVS Subcommi ee on E hics o Li e and Heal h Sciences
RCT andomized con olled ial
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