Conditions: Major Depressive Disorder
Keywords: Depression Geriatrics Elderly MRI Antidepressants
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 95
Healthy volunteers: no

Brief summary:
It can be difficult to achieve remission in individuals with late-life depression (LLD) and they often require aggressive treatment. This challenge is in part due to age-related vascular changes that are common in LLD. Successful antidepressant treatment involve changes across affective, cognitive, and default mode networks. We hypothesize that in LLD, vascular disease adversely affects response to antidepressants by disrupting connectivity of these networks. The primary goal of this project is to characterize how focal vascular damage affects regional connectivity and response to antidepressants. Based on past work and pilot data, we a priori focus on the cingulum bundle and uncinate fasciculus. These key fiber bundles connect frontal, temporal, and cingulate regions involved in cognition and affective responses. Our central hypothesis is that ischemic damage to the cingulum bundle and uncinate fasciculus contributes to structural and functional connectivity deficits of those tracts. This results in a disconnection effect that alters the function of connected regions. In turn, this increases the risk of a poor response to antidepressants.

Our approach is to enroll up to 130 adults over age 60 years with a diagnosis of Major Depressive Disorder. Subjects will complete clinical evaluation, cognitive testing, and MRI/functional MRI (fMRI) sessions, including an fMRI emotional oddball task that includes attentional and affective components. Participants will be stratified by cerebral lesion severity and randomized in a 2:1 ratio to a double-blinded 8-week trial of escitalopram or matching placebo. Those who do not remit will transition to an 8-week trial of open-label bupropion, an antidepressant with a different mechanism of action. This will allow us to determine if different and distinct circuit deficits affect response to antidepressants with different mechanisms of action while also accounting for the placebo response.

Detailed description:
Individuals with late-life depression (LLD) experience high levels of disability, mortality, and poor responses to antidepressants. The MRI hallmark of 'vascular depression' in this population is significant ischemic white matter lesion (WML) severity, a finding associated with poor antidepressant outcomes. Despite observations of diffuse white matter disease in LLD, we propose in our "disconnection hypothesis" that focal damage to fiber tracts negatively affects the function of connected regions, resultantly contributing to cognitive deficits and clinical symptoms such as depression severity and negativity bias. Focal WMLs may also reduce the likelihood of an antidepressant response when the specific antidepressant used acts on neurotransmitter systems projecting through the damaged fiber tract. This implies that the effect of tract damage on clinical response may differ between drugs with different mechanism of action.

We propose that the cingulum bundle (CB) and uncinate fasciculus (UF) are key tracts in LLD as they are components of cognitive, affective and default mode networks and contain monoamine neurotransmitter projections. Supporting our model, past work implicates CB and UF deficits in LLD and our new pilot data associates tract damage with poor antidepressant response.

In a cohort of up to 130 depressed elders we will test our central hypotheses: a) focal CB and UF WMLs disrupt connectivity and function of connected regions and contribute to cognitive deficits and affective symptoms; and b) antidepressants acting on neurotransmitter systems projecting through these tracts will be less effective.

Overall Study Design: After obtaining informed consent, we will assess for eligibility. Individuals who meet eligibility criteria will complete neuropsychological testing and a one-hour magnetic resonance imaging (MRI). Subjects will then be randomized in a 2:1 ratio to receive either blinded escitalopram or identical placebo. After 8 weeks of study drug, they will be assessed for remission. Those whose depression has remitted will end their study participation. Those who remain symptomatic will be transitioned to open-label bupropion for 8 weeks, after which their participation will end. We will work with participants on plans for clinical care after the study and will offer two additional visits to facilitate that transition.

Specific Aim 1: To characterize the effect of cingulum bundle (CB) and uncinate fasciculus (UF) WMLs on tract connectivity, function of connected regions, and the cognitive and affective presentation of LLD.

Hypothesis 1: Greater CB WML volume is associated with a) reduced resting-state connectivity of frontal, temporal, and cingulate regions and b) deficits in attention, memory and processing speed.

Hypothesis 2: Greater UF WML volume is associated with a) reduced resting state functional connectivity between frontocingulate and medial temporal regions, and b) greater depression severity and negativity bias.

Exploratory Hypothesis: Greater CB WML volume is associated with failure of anterior and posterior default mode network nodes to deactivate during attentional components of the fMRI task. Greater UF WML volume is associated with greater medial temporal reactivity during the functional MRI task.

Specific Aim 2: To determine whether deficits in tract structural / functional connectivity predict nonremission to antidepressant treatments and if these relationships vary based on antidepressant mechanism of action.

Hypothesis 3: Nonremission to escitalopram will be predicted by: a) greater WML volume in the CB and UF, and b) reduced resting functional connectivity between structures connected by the CB and UF. Greater WML severity and reduced functional connectivity in these tracts will not significantly predict response to placebo.

Hypothesis 4: Nonremission to bupropion will be predicted by a) greater WML volume in the UF but not CB, and b) reduced resting functional connectivity deficits between structures connected by the UF but not CB.

Exploratory Aims: Expl. Aim 1) To determine if specific cognitive measures may serve as markers of focal tract WML damage. Expl. Aim 2) To use whole-brain multimodal imaging approaches to examine how connectivity differences in other brain regions may also predict nonremission to antidepressants.

Arms:
arm 1: 8 weeks of blinded escitalopram, followed by 8 weeks of open-label bupropion xl for nonremitters arm 2: 8 weeks of blinded placebo, followed by 8 weeks of open-label bupropion xl for nonremitters.

Interventions: intervention 1: Escitalopram intervention 2: Bupropion XL
Intervention descriptions: intervention 1: Escitalopram 10-20mg daily intervention 2: Bupropion XL 150-450mg daily

Protocol document:
Prot_SAP_000.pdf: 
Pr ot o c ol V er si o n: 2. 0  
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Titl e: C o n n e cti vit y Aff e cti n g t h e A nti d e pr e s s a nt R e s p o n s e ( C A A R E)  
St u d y Pr ot o c ol  
 
Cli ni c altri al s. g o v I d e ntifi er: N C T 0 2 3 3 2 2 9 1  
 
NI H Gr a nt: R 0 1 M H 1 0 2 2 4 6  
NI H Gr a nt Titl e: N e ur al C o n n e cti vit y Aff e cti n g t h e A nti d e pr e s s a nt R e s p o n s e: T e sti n g a L e si o n M o d el  
 
D o c u m e nt D at e: 4/ 1 0/ 2 0 2 0  
 
 


Pr ot o c ol V er si o n: 2. 0  
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C o n n e cti vit y Aff e cti n g t h e A nti d e pr e s s a nt R E s p o n s e ( T h e C A A R E st u d y)  
 
NI H Gr a nt: R 0 1 M H 1 0 2 2 4 6  
NI H Gr a nt Titl e: N e ur al C o n n e cti vit y Aff e cti n g t h e A nti d e pr e s s a nt R e s p o n s e: T e sti n g a L e si o n M o d el  
Cli ni c altri al s. g o v I d e ntifi er: N C T 0 2 3 3 2 2 9 1  
 
PI:  
W arr e n D. T a yl or, M D, M H S c  
D e p art m e nt of P s y c hi atr y  
V a n d er bilt U ni v er sit y  M e di c al C e nt er  
1 6 0 1 2 3 r d A v e n u e  S o ut h  
N a s h vill e T N 3 7 2 1 2  
 
 
1. 0 B A C K G R O U N D : 
I n di vi d u al s wit h l at e-lif e d e pr e s si o n ( L L D) e x p eri e n c e hi g h l e v el s of di s a bilit y, m ort alit y, a n d p o or r e s p o n s e s t o 
a nti d e pr e s s a nt s. A g e -r el at e d w hit e m att er di s e a s e i s c h ar a ct eri sti c of L L D a n d c o ntri b ut e s t o t h e s e p o or 
o ut c o m e s (1 ).  Alt h o u g h t h e u n d erl yi n g m e c h a ni s m s ar e n ot w ell e st a bli s h e d, w hit e m att er di s e a s e m a y  
c o ntri b ut e t o L L D b y a d v er s el y aff e cti n g c o g niti v e, aff e cti v e, a n d d ef a ult m o d e n et w or k s. T hi s pr oj e ct’ s pri m ar y 
g o al s  ar e t o c h ar a ct eri z e w h et h er  f o c al v a s c ul ar d a m a g e t o s p e cifi c w hit e m att er tr a ct s: a) aff e ct s n e ur al cir c uit  
c o n n e cti vit y & f u n cti o n, b) i nfl u e n c e s cli ni c a l pr e s e nt ati o n, a n d c) pr e di ct s p o or r e s p o n s e  t o a nti d e pr e s s a nt s. 
T h e M RI h all m ar k of ‘ v a s c ul ar d e pr e s si o n’ i s si g nifi c a nt  i s c h e mi c w hit e m att er l e si o n ( W M L) s e v erit y (2 ), a  
fi n di n g a s s o ci at e d wit h p o or a nti d e pr e s s a nt o ut c o m e s. D e s pit e o b s er v ati o n s of diff u s e w hit e m att er di s e a s e i n 
L L D, w e pr o p o s e i n  o ur “ di s c o n n e cti o n h y p ot h e si s” (3 ) t h at f o c al d a m a g e t o fi b er tr a ct s n e g ati v el y aff e ct s t h e 
f u n cti o n of c o n n e ct e d r e gi o n s, r e s ult a ntl y c o ntri b uti n g t o c o g niti v e  d efi cit s  a n d cli ni c al  s y m pt o m s s u c h a s 
d e pr e s si o n s e v erit y a n d n e g ati vit y  bi a s . F o c al W M L s m a y al s o r e d u c e t h e li k eli h o o d of a n a nti d e pr e s s a nt 
r e s p o n s e w h e n t h e s p e cifi c a nti d e pr e s s a nt u s e d a ct s o n n e ur otr a n s mitt er s y st e m s pr oj e cti n g t hr o u g h t h e 
d a m a g e d fi b er tr a ct .  T hi s i m pli e s t h at t h e eff e ct of tr a ct d a m a g e o n cli ni c al r e s p o n s e m a y diff er b et w e e n dr u g s 
wit h diff er e nt m e c h a ni s m of a cti o n .  W e pr o p o s e t h at t h e ci n g ul u m b u n dl e ( C B)  a n d u n ci n at e f a s ci c ul u s  
 
( U F) ar e k e y tr a ct s i n L L D a s t h e y  ar e  c o m p o n e nt s of c o g niti v e, aff e cti v e a n d d ef a ult m o d e n et w or k s  a n d 
c o nt ai n m o n o a mi n e n e ur otr a n s mitt er pr oj e cti o n s.  S u p p orti n g o ur m o d el, p a st w or k  i m pli c at e s C B a n d U F 
d efi cit s i n L L D (4 -7 ) a n d o ur r e c e ntl y p u bli s h e d d at a  a s s o ci at e s tr a ct d a m a g e i n t h e C B wit h p o or  
a nti d e pr e s s a nt r e s p o n s e  (8 ).  
T hi s st u d y h a s br o a d si g nifi c a n c e  f or el u ci d ati n g h o w v a s c ul ar f a ct or s i nfl u e n c e t h e o c c urr e n c e a n d 
c o ur s e of L L D.  It pr o vi d e s a s ci e ntifi c o p p ort u nit y  t o u s e a n e ur oi m a gi n g fi n di n g of k n o w n p at h ol o g y ( W M L s) t o 
e x a mi n e  h o w cir c uit d efi cit s a d v er s el y aff e ct a nti d e pr e s s a nt  r e s p o n s e. I m p ort a ntl y, cli ni c al tr a n sl ati o n  of t hi s 
w or k m a y  g ui d e i n di vi d u ali z e d tr e at m e nt.  K n o wl e d g e of cir c uit -r es p o n s e r el ati o n s hi p s m a y i nf or m 
a nti d e pr e s s a nt s el e cti o n or t h e i d e ntifi c ati o n of i n di vi d u al s li k el y t o b e tr e at m e nt-r efr a ct or y. W e pr o p o s e t h at w e 
m a y tr a n sl at e t hi s w or k i nt o cli ni c al u s e b y li n ki n g i m p air m e nt i n cir c uit s a n d tr a ct s wit h p erf or m a n c e o n s p e cifi c 
c o g niti v e m e a s ur e s.  S u c h m e a s ur e s c a n t h e n b e u s e d a s m ar k er s of f o c al tr a ct d a m a g e. 
 
2. 0 R A TI O N A L E a n d S P E CI FI C AI M S : 
I n a c o h ort of 1 30 d e pr e s s e d el d er s  w e will t e st o ur  c e ntr al h y p ot h e s e s:  a) f o c al C B a n d U F W M L s  
di sr u pt  c o n n e cti vit y a n d f u n cti o n  of c o n n e ct e d r e gi o n s a n d c o ntri b ut e t o c o g ni ti v e d efi cit s a n d 
aff e cti v e s y m pt o m s; a n d b) a nti d e pr e s s a nt s a cti n g o n n e ur otr a n s mitt er s y st e m s pr oj e cti n g t hr o u g h 
t h e s e tr a ct s will b e l e s s eff e cti v e. W e will e x a mi n e h o w n o v el m e a s ur e s  of tr a ct -s p e cifi c W M L v ol u m e s ar e 
a s s o ci at e d wit h n e ur al  c o n n e cti vit y  (u si n g  r e sti n g st at e f M RI), r e a cti vit y t o c o g niti v e & aff e cti v e sti m uli ( u si n g a 
f M RI t a s k), & cli ni c al pr e s e nt ati o n. Aft er M RI , p arti ci p a nt s will b e str atifi e d b y W M L v ol u m e  a n d r a n d o mi z e d t o 
bli n d e d e s cit al o pr a m ( 5 H T) or pl a c e b o .  P arti ci p a nt s w h o d o n ot r e mit i n t hi s i niti al p h a s e will t h e n r e c ei v e 
o p e n -l a b el b u pr o pi o n ( D A/ N E).  T h e s e dr u g s aff e ct diff er e nt n e ur otr a n s mitt er s y st e m s wit h di sti n ct pr oj e cti o n 
p at h w a y s. T hi s d e si g n will all o w u s t o e x a mi n e  b ot h dr u g a n d pl a c e b o r e s p o n s e s w hil e al s o t e sti n g  w h et h er  
di s cr et e n e ur al cir c uit  d efi cit s diff er e nti all y aff e ct dr u g r e s p o n s e.  
 
S p e cifi c Ai m 1 : T o c h ar a ct eri z e t h e eff e ct of ci n g ul u m b u n dl e ( C B) a n d u n ci n at e f a s ci c ul u s ( U F) W M L s o n  


Pr ot o c ol V er si o n: 2. 0  
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tr a ct c o n n e cti vit y, f u n cti o n of c o n n e ct e d r e gi o n s, a n d t h e c o g niti v e a n d aff e cti v e pr e s e nt ati o n of L L D  ( Fi g 1 & 2). 
H y p ot h e si s 1 : Gr e at er C B W M L v ol u m e i s a s s o ci at e d wit h a) r e d u c e d r e sti n g-st at e c o n n e cti vit y of fr o nt al, 
te m p or al, a n d ci n g ul at e r e gi o n s a n d b) d efi cit s i n att e nti o n, m e m or y a n d pr o c e s si n g s p e e d.  
H y p ot h e si s 2 : Gr e at er U F  W M L v ol u m e i s a s s o ci at e d wit h a) r e d u c e d r e sti n g st at e f u n cti o n al c o n n e cti vit y 
b et w e e n fr o nt o ci n g ul a t e a n d m e di al t e m p or al r e gi o n s, a n d b) gr e at er d e pr e s si o n s e v erit y a n d n e g ati vit y bi a s.  
E x pl or at or y H y p ot h e si s : Gr e ater C B W M L v ol u m e i s a s s o ci at e d wit h f ail ur e of a nt eri or a n d p o st eri or D M N 
n o d e s t o d e a cti v at e d uri n g att e nti o n al c o m p o n e nt s of t h e f M RI  t a s k.  Gr e at er U F W M L v ol u m e  i s 
a s s o ci at e d wit h  gr e at er m e di al t e m p or al r e a cti vit y d uri n g aff e cti v e c o m p o n e nt s of t h e f M RI t a s k.  
 
S p e cifi c Ai m 2 : T o d et er mi n e w h et h er d efi cit s i n tr a ct str u ct ur al / f u n cti o n al c o n n e cti vit y pr e di ct n o nr e mi s si o n 
t o a nti d e pr e s s a nt tr e at m e nt s a n d if t h e s e r el ati o n s hi p s v ar y b a s e d o n a nti d e pr e s s a nt m e c h a ni s m of a cti o n. 
H y p ot h e si s 3 :  N o nr e mi s si o n t o e s cit al o pr a m will b e pr e di ct e d b y: a) gr e at er W M L v ol u m e i n t h e C B a n d U F, 
a n d b) r e d u c e d r e sti n g f u n cti o n al c o n n e cti vit y b et w e e n str u ct ur e s c o n n e ct e d b y t h e C B a n d U F.  Gr e at er W M L 
s e v erit y a n d r e d u c e d f u n cti o n al c o n n e cti vit y i n t h e s e tr a ct s will n ot si g nifi c a ntl y pr e di ct r e s p o n s e t o pl a c e b o.  
H y p ot h e si s 4 :  N o nr e mi s si o n t o b u pr o pi o n will b e pr e di ct e d b y a) gr e at er W M L v ol u m e i n t h e U F b ut n ot C B, 
a n d b) r e d u c e d r e sti n g f u n cti o n al c o n n e cti vit y d efi cit s b et w e e n str u ct ur e s c o n n e ct e d b y t h e U F b ut n ot C B.  
 
E x pl or at or y Ai m s : E x pl. Ai m 1) T o d et er mi n e if s p e cifi c c o g niti v e m e a s ur e s m a y s er v e a s m ar k er s  of f o c al 
tr a ct W M L d a m a g e. E x pl. Ai m  2)  T o u s e w h ol e -br ai n m ulti m o d al i m a gi n g a p pr o a c h e s  t o e x a mi n e h o w 
c o n n e cti vit y diff er e n c e s i n ot h er br ai n r e gi o n s m a y al s o pr e di ct n o nr e mi s si o n t o a nti d e pr e s s a nt s.  
 
F or e x pl or at or y a n al y s e s, w e will al s o r e cr uit 3 0 e l d er s wit h n o p s y c hi atri c hi st or y.  D at a fr o m t hi s p o p ul ati o n 
will h el p u s u n d er st a n d w h et h er o ur n e ur al a n d c o g niti v e fi n di n g s i n d e pr e s si o n r e pr e s e nt diff er e n c e s fr o m 
w h at i s s e e n i n h e alt h y a gi n g, or w h et h er o ur o b s er v ati o n s i n d e pr e s s e d el d er s ar e wit h i n t h e r a n g e of n or m al 
a gi n g.  T hi s will b e i m p ort a nt f or d at a i nt er pr et ati o n a n d pl a n ni n g f or f ut ur e pr oj e ct s.  
 
3. 0 A NI M A L S T U DI E S & P R E VI O U S H U M A N S T U DI E S  
3. 1 . L at e lif e d e pr e s si o n a n d v a s c ul ar di s e a s e: L at e -lif e d e pr e s si o n (L L D ) i s c h ar a ct eri z e d b y p o or 
tr e at m e nt r e s p o n s e s al o n g wit h i n cr e a s e d m or bi dit y, m ort alit y a n d di s a bilit y (9 ,1 0 ). A si g nifi c a nt b o d y of 
r e s e ar c h s u p p ort s t h e r ol e of v a s c ul ar di s e a s e i n t h e p at h o g e n e si s of L L D.   T hi s i nf or m e d t h e “ v a s c ul ar  
d e pr e s si o n ” h y p ot h e si s, w hi c h p o sit s t h at v a s c ul ar di s e a s e, c h ar a ct eri z e d b y gr e at er diff u s e h y p eri nt e n s e 
w hit e m att er l e si o n ( W M L ) s e v erit y o n M RI, m a y pr e di s p o s e  t o or p er p et u at e L L D (1 -3 ).  Alt h o u g h n ot all 
st u di e s a gr e e (1 1 -1 5 ), gr e at er W M L s e v erit y i s g e n er all y a s s o ci at e d wit h p o or er a nti d e pr e s s a nt r e s p o n s e (1 6 -
2 1 ).  I n o ur di s c o n n e cti o n h y p ot h e si s  (3 ), w e pr o p o s e t h at t h e f u n cti o n al a n d cli ni c al si g nifi c a n c e of W M L s 
d e p e n d s o n w hi c h  n e ur al cir c uit s ar e  di sr u pt e d .   
 
3 .2 . Cir c uit s i n L L D : T h e u n ci n at e f a s ci c ul u s (U F ) a n d ci n g ul u m b u n dl e (C B ) ar e criti c al fi b er tr a ct s wit hi n 
f u n cti o n al n et w or k s i m pli c at e d i n M aj or D e pr e s si v e Di s or d er ( M D D; T a bl e 1 ; S e ct A. 3).  T h e U F  i s i n v ol v e d i n 
m e m or y a n d e m oti o n al pr o c e s si n g (2 2 ).  It r u n s wit hi n t h e t e m p or al st e m a n d c o n n e ct s t h e a m y g d al a a n d 
hi p p o c a m p u s wit h t h e m e di al a n d l at er al or bit ofr o nt al c ort e x (2 3 -2 8 ). T h e C B  i s a p at h w a y s u p eri or t o t h e 
c or p u s c all o s u m i n v ol v e d i n att e nti o n, m e m or y, a n d e m oti o n al r e g ul ati o n (2 9 ).  It c o nt ai n s fi b er s ori gi n ati n g 
fr o m t h e ci n g ul at e g yr u s, t h al a m u s, a n d fr o nt o p ari et al ar e a s, pr oj e cti n g t o ot h er ci n g ul at e r e gi o n s, t h e 
pr efr o nt al c ort e x, pr e s u bi c ul u m, pr e c u n e u s, a m y g d al a, a n d hi p p o c a m p u s (2 6 ,2 7 ,2 9 -3 1 ).  
W or k fr o m o ur gr o u p a n d ot h er s s h o w s t h at L L D  i s a s s o ci at e d wit h gr e at er W M L s e v erit y i n di s cr et e tr a ct s 
i n cl u di n g t h e ci n g ul u m b u n dl e  (C B ) a n d u n ci n at e f a s ci c ul u s (U F ) (4 -7 ). Si mil arl y, w or k u si n g diff u si o n t e n s or 
i m a gi n g al s o a s s o ci at e s d e pr e s si o n wit h d efi cit s i n t h e U F (7 ,3 2 -3 4 ) a n d C B (3 2 ,3 4 ).  Si mil arl y, o ur r e c e ntl y 
p u bli s h e d d at a d e m o n str at e s t h at gr e at er W M L s e v erit y i n t h e C B i s a s s o ci at e d wit h p o or a nti d e pr e s s a nt 
r e s p o n s e (8 ).  T h e s e d at a s u p p ort t h at d a m a g e t o t h e C B a n d U F c o ntri b ut e s t o t h e o c c urr e n c e a n d 
pr e s e nt ati o n of L L D . 


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3 . 2. a F u n cti o n al N et w or k s i n L L D: Eff e ct of W M L s: 
Alt h o u g h s o m e w ell -d e si g n e d st u di e s h a v e n ot f o u n d alt er e d 
f u n cti o n al c o n n e cti vit y i n L L D (3 2 ), ot h er s r e p ort t h at L L D i s 
a s s o ci at e d wit h alt er e d c o n n e cti vit y i n aff e cti v e, c o g niti v e, 
a n d d ef a ult m o d e ( D M N ) n et w or k s (3 5 -4 1 ). Gr e at er W M L 
s e v erit y a p p e ar s t o i m p air c o n n e c ti vit y a n d f u n cti o n of t h e s e 
n et w or k s (4 1 -4 3 ).  I m p ort a ntl y, s o m e of t h e s e st u di e s 
o b s er v e d i n cr e a s e d f u n cti o n al c o n n e cti vit y i n L L D. A s h a s 
b e e n o b s er v e d i n M D D (4 4 ), o b s er v ati o n s of i n cr e a s e d 
c o n n e cti vit y c a n b e r el at e d t o d efi cit s  i n str u ct ur al 
c o n n e cti vit y, p arti c ul arl y if str u ct ur al d efi cit s o c c ur i n 
r e g ul at or y c o n n e cti o n s. 
A r e c e nt r e p ort s s h o w s t h at D M N cir c uit d efi cit s i n L L D 
aff e ct t h e a nti d e pr e s s a nt r e s p o n s e.  C o m p ar e d wit h 
tr e at m e nt-n o n r e s p o n si v e s u bj e ct s, a nti d e pr e s s a nt 
r e s p o n d er s e x hi bit gr e at er  pr e -tr e at m e nt c o n n e cti vit y  
b et w e e n t h e p o st eri or ci n g ul at e c ort e x a n d m e di al P F C (4 5 ).  
T hi s s u p p ort s o ur t h e or eti c al m o d el  (Fi g. 2 c ). 
 
3 .3 . N et w or k  d efi cit s  i n l at e-lif e d e pr e s si o n: A t h e or eti c al 
m o d el : S u m m ari z e d b y S h eli n e et al. (4 6 ), M D D i s 
c h ar a c t eri z e d b y alt er e d f u n cti o n of t hr e e k e y n et w or k s.  
T h e s e n et w or k s h a v e di sti n ct r ol e s  wit h s o m e a n at o mi c al 
o v erl a p (4 7 ).  T h e U F a n d C B ar e criti c al fi b er tr a ct s wit hi n 
t h e s e n et w or k s. 
3 . 3. a. T h e aff e cti v e n et w or k  ( A N) m e di at e s e m oti o n al 
pr o c e s si n g a n d i s i n v ol v e d i n a ut o n o mi c a n d vi s c er al 
r e g ul ati o n.  It c o n si st s of t h e aff e cti v e di vi si o n of t h e a nt eri or 
ci n g ul at e c ort e x ( A C C) , al o n g wit h it s c o n n e cti o n s t o t h e 
a m y g d al a, e nt or hi n al c ort e x, n u cl e u s a c c u m b e n s, a n d o t h er 
li m bi c str u ct ur e s.  Alt er e d A N a cti vit y i n M D D i s w ell 
d o c u m e nt e d, i n cl u di n g i n cr e a s e d r e a cti vit y t o n e g ati v e 
sti m uli  (4 8 ,4 9 ).  
T h e  U F a n d C B ar e i n v ol v e d i n t h e A N ( Fi g ur e s 1 a n d 
2 a).  Di sr u pti o n of t h e s e tr a ct s aff e ct s fr o nt o ci n g ul at e c o ntr ol 
o v er a m y g d al a r e a cti vit y. I n t ur n, a m y g d al a h y p er a cti vit y i s 
a s s o ci at e d wit h gr e at er d e pr e s si o n s e v erit y (5 0 ) a n d a n e g ati v e bi a s i n pr o c e s si n g a n d i nt er pr eti n g e m oti o n al 
sti m uli (5 1 ,5 2 ).   W e a nti ci p at e t h at W M L s i n t h e U F a n d C B will c o ntri b ut e t o gr e at er a m y g d al a r e a cti vit y t o 
n e g ati v e e m oti o n al sti m uli  (r e vi e w e d in (4 9 )).  Si mil arl y, gr e at er W M L s e v erit y i n t h e s e tr a ct s will b e 
a s s o ci at e d wit h gr e at er o ut -of -s c a n n er d e pr e s si o n s e v erit y  a n d n e g ati vit y bi a s .   
3 . 3. b. T h e c o g niti v e c o ntr ol n et w or k  ( C C N) c o n si st s of fr o nt al a n d pari et al r e gi o n s, i n cl u di n g t h e d or s ol at er al 
pr efr o nt al c ort e x a n d d or s al a nt eri or ci n g ul at e c ort e x.  T h e C C N m o d ul at e s att e nti o n al pr o c e s s e s a n d w or ki n g  
m e m or y, i s i n v ol v e d i n d e ci si o n-m a ki n g  a n d c o nfli ct r e s ol uti o n a n d i s i m p air e d i n M D D (3 8 ,5 3 ).  T h e a nt eri or  
C B c o nt ai n s  c o n n e cti o n s b et w e e n d or s al C C N r e gi o n s  ( Fi g 2 b) (5 4 ,5 5 ).  A nt eri or C B di sr u pti o n  m a y c o ntri b ut e 
t o d e cr e a s e d c o n n e cti vit y b et w e e n C C N  r e gi o n s i n L L D (3 8 ), w hi c h i s c orr el at e d wit h p o or a nti d e pr e s s a nt 
r e s p o n s e (3 8 ). Alt er e d C B mi cr o str u ct ur e  i s a s s o ci at e d wit h e x e c uti v e d y sf u n cti o n  (3 4 ,5 6 ), w hi c h i n L L D i s 
a s s o ci at e d wit h p o or tr e at m e nt r e s p o n s e (2 1 ,5 7 ).  H o w e v er, alt er e d U F mi cr o str u ct ur e i s al s o a s s o ci at e d wit h 
e x e c uti v e d y sf u n cti o n  (3 4 ,5 8 ,5 9 ); t hi s m a y b e d u e t o di sr u pt e d v e ntr al hi p p o c a m p u s –  P F C c o n n e cti vit y (6 0 ). 
3 . 3. c. T h e d ef a ult m o d e n et w or k  ( D M N) (4 7 ,6 1 ) i s i m p ort a nt i n s elf-r ef er e nti al a cti viti e s a n d m or e a cti v e  at 
r e st (4 7 ). T h e D M N c o n si st s of wi d el y di stri b ut e d el e m e nt s b ut i s di vi d e d i nt o a nt eri or a n d p o st eri or  n o d e s  (6 1 ) 
t h at oft e n a ct i n d e p e n d e ntl y (6 2 ).  Th e p o st eri or n o d e  i n cl u d e s t h e p o st eri or ci n g ul at e c ort e x a n d pr e c u n e u s  
w hil e t h e a nt eri or n o d e i n cl u d e s t h e a nt eri or ci n g ul at e a n d v e ntr o m e di al P F C. R e d u c e d f u n cti o n al c o n n e cti vit y 
b et w e e n D M N n o d e s m a y c o ntri b ut e t o diffi c ulti e s d e a cti v ati n g t h e D M N d uri n g t a s k s (3 8 ,4 6 ,6 3 ,6 4 ).  
I n M D D, t h e D M N oft e n d o e s n ot d e a cti v at e  d uri n g aff e cti v e a n d c o g niti v e c h all e n g e s, c o ntri b uti n g t o 


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m al a d a pti v e c o g niti v e pr o c e s s e s (6 1 ,6 5 ).  I n M D D w e o b s er v e a di s s o ci ati o n b et w e e n  a nt eri or a n d p o st eri or 
D M N n o d e s  (6 6 ) w hil e wit hi n -n o d e f u n cti o n al c o n n e cti vit y i s i n cr e a s e d (3 8 ,4 6 ,6 3 ,6 4 ).  A s r e d u c e d f u n cti o n al 
c o n n e cti vit y i s r el at e d t o alt er e d C B str u ct u r e (6 7 ,6 8 ), w e pr o p o s e t h at W M L s i n t h e C B a dj a c e nt t o t h e 
ci n g ul at e g yr u s  m a y di sr u pt c o m m u ni c ati o n b et w e e n D M N n o d e s. T hi s w o ul d i m p air  a nt eri or -p o st eri or 
c o n n e cti vit y , r e s ulti n g i n diffi c ult y c o or di n ati n g d e a cti v ati o n of t h e D M N d uri n g t a s k s (6 1 ).  T hi s c o ntri b ut e s t o 
d efi cit s i n att e nti o n  (6 9 ,7 0 ) a n d pr o c e s si n g s p e e d (5 9 ,7 1 -7 3 ), d efi cit s a s s o ci at e d wit h p o or a nti d e pr e s s a nt 
r e s p o n s e (2 1 ,5 7 ). A d diti o n all y , da m a g e t o t h e C B i n t h e r e gi o n of t h e hi p p o c a m p u s  m a y h a v e f urt h er eff e ct s. 
W M L s i n t hi s r e gi o n m a y di sr u pt hi p p o c a m p u s -p o st eri or ci n g ul at e  c o n n e cti vit y (3 1 ,4 7 ,7 4 ) r e s ulti n g i n p o or er 
e pi s o di c m e m or y p erf or m a n c e (7 5 -7 7 ). T hi s r e s ult s i n e pi s o di c m e m or y  d efi cit s  t h at ar e al s o a s s o ci at e d wit h 
p o or L L D a nti d e pr e s s a nt r e s p o n s e s (2 1 ) ( Fi g ur e 2. c). 
 
3 .4 . A nti d e pr e s s a nt s wit h diff er e nt m e c h a ni s m s of a cti o n : A nti d e pr e s s a nt tr e at m e nt c h a n g e s br ai n 
m et a b oli s m (7 8 -8 2 ).  H o w e v er, anti d e pr e s s a nt s wit h diff er e nt m e c h a ni s m s of a cti o n  h a v e diff er e nt eff e ct s o n 
n e ur al cir c uit  c o n n e cti vit y (8 3 ,8 4 ) or n e ur al a cti vit y d uri n g t a s k s  (8 5 ,8 6 ).   
T h e r el ati o n s hi p b et w e e n n e ur al cir c uit d efi cit s  a n d t h e a nti d e pr e s s a nt r e s p o n s e m a y d e p e n d o n t h e dr u g’ s 
s p e cifi c m e c h a ni s m of a cti o n . W e h y p ot h e si z e t h at  tr a ct d a m a g e pr e di ct s n onr e s p o n s e t o a nti d e pr e s s a nt s t h at 
aff e ct n e ur otr a n s mitt er s y st e m s pr oj e cti n g t hr o u g h t h at tr a ct.  S er ot o n er gi c n e ur o n s pr oj e ct wi d el y t hr o u g h t h e 
C B (8 7 ), b ut al s o t o t h e or bit ofr o nt al c ort e x a n d m e di al t e m p or al l o b e (8 8 -9 0 ), s u g g e sti n g U F i n v ol v e m e nt.  
N or a dr e n er gi c pr oj e cti o n s l ar g el y o v erl a p  wit h s er ot o n er gi c i n n er v ati o n  (9 1 ), i n cl u di n g C B pr oj e cti o n s (9 2 ). I n 
c o ntr a st, d o p a mi n er gi c n e ur o n s  h a v e di s cr et e p at h w a y s (9 3 -9 6 ). D o p a mi n er gi c m e s o c orti c al a n d me s oli m bi c 
fi b er s m a y p a s s t hr o u g h t h e U F (9 7 ), b ut c om p ar e d t o s er ot o ni n or n or e pi n e p hri n e, h a v e l e s s C B pr oj e cti o n s 
(9 8 ). T h u s dr u g s aff e cti n g s er ot o ni n a n d n or e pi n e p hri n e m a y r e q uir e i nt a ct c o n n e cti vit y i n b ot h t h e C B a n d U F, 
w hil e d o p a mi n er gi c a g e nt s m a y d e p e n d l e s s o n t h e C B.  
 
4. 0 E N T R Y C RI T E RI A  
W e pl a n t o e nr oll a c o h ort of 2 0 0  i n di vi d u al s t o m e et g o al s of h a vi n g 1 3 0 e v al u a bl e s u bj e ct s.  P arti ci p a nt s will 
m e et  D S M -I V-T R crit eri a f or M D D, si n gl e e pi s o d e, r e c urr e nt, or c hr o ni c. W e will n ot b e e nr olli n g v ul n er a bl e 
p o p ul ati o n s, s p e cifi c all y pr e g n a nt w o m e n, c hil dr e n, pri s o n er s, or i n stit uti o n ali z e d i n di vi d u al s.  W e al s o will n ot 
e nr oll s u bj e ct s i n c a p a bl e of pr o vi di n g t h eir o w n c o n s e nt.  S h o ul d a p ot e nti al s u bj e ct pr e s e nt w h er e t h er e i s a 
c o n c er n ( eit h er b y a st u d y cli ni ci a n or st aff m e m b er) a b o ut t h eir a bilit y t o u n d er st a n d st u d y pr o c e d ur e s a n d 
p r o vi d e m e a ni n gf ul c o n s e nt, t h eir c o g niti v e a bilit y a n d u n d er st a n di n g will b e e v al u at e d b y a st u d y d o ct or .  If 
t h er e i s a n y c o n c er n t h at t h e i n di vi d u al m a y b e i m p air e d, t h e y will n ot b e e nr oll e d i n t h e st u d y.  T h e r ati o n al e 
will b e pr o vi d e d t o t h e i n di vi d u a l a s w ell a s hi s or h er f a mil y m e m b er s.  R ef err al s f or f urt h er e v al u ati o n, 
i n cl u di n g ur g e nt or e m er g e nt e v al u ati o n, will b e m a d e a s n e e d e d a n d cli ni c all y w arr a nt e d. 
 
M e n a n d w o m e n of all r a c e s / et h ni citi e s ar e eli gi bl e.  
 
D e pr e s s e d C o h ort:  
I n cl u si o n Crit eri a: 
1)  A g e 6 0 y e ar s or ol d er.  
2)  C urr e nt di a g n o si s of m aj or d e pr e s si v e di s or d er ( D S M -I V-T R), si n gl e e pi s o d e, r e c urr e nt or c hr o ni c, 
wit h o ut p s y c h oti c f e at ur e s, a s d et e ct e d b y MI NI a n d cli ni c al e x a m.  
3)  Mi ni m u m M A D R S s c or e ≥ 1 5.  
4)  Mi ni -M e nt al St at e E x a m  ≥ 2 4.  
5)  Fl u e nt i n E n gli s h.  
 
E x cl u si o n Crit eri a:  
Di a g n o sti c I s s u e s:  
1)  C urr e nt or p a st di a g n o s e s of ot h er A xi s I p s y c hi atri c di s or d er s, e x c e pt f or g e n er ali z e d a n xi et y di s or d er 
( G A D) s y m pt o m s o c c urri n g d uri n g a d e pr e s si v e e pi s o d e 
2)  Hi st or y of al c o h ol or dr u g d e p e n d e n c e or a b u s e i n t h e l a st t hr e e y e ar s  
3)  Hi st or y of d e v el o p m e nt al di s or d er or I Q s c or e < 7 0  
4)  Pr e s e n c e of a c ut e s ui ci d al i d e ati o n, d efi n e d a s a “ y e s” r e s p o n s e t o it e m s 3, 4, or 5 o n t h e C -S S R S  
5)  A c ut e gri ef ( < 1 m o nt h)  


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6)  C urr e nt or p a st p s y c h o si s  
M e di c al I s s u e s: 
7)  Pri m ar y n e ur ol o gi c al di s or d er, i n cl u di n g b ut n ot li mit e d t o d e m e nti a, str o k e, br ai n t u m or s, e pil e p s y, 
P ar ki n s o n’ s di s e a s e, or d e m y eli n ati n g di s e a s e s  
8)  M RI c o ntr ai n di c ati o n s  
9)  A n y p h y si c al or i nt ell e ct u al di s a bilit y a d v er s el y aff e cti n g a bilit y t o c o m pl e t e a s s e s s m e nt s 
1 0)  C urr e nt pr e g n a n c y or c a p a bl e of b e c o mi n g pr e g n a nt  ( d efi n e d a s a bilit y t o h a v e c hil dr e n [i. e., h a s n ot 
h a d a h y st er e ct o m y or bil at er al o o p h or e ct o m y] a n d i s n ot cl e arl y p o st m e n o p a u s al [ > 1 y e ar of 
a m e n orr h e a])  
A nti d e pr e s s a nt Tr e at m e nt I s s u e s : 
1 1)  E C T i n l a st 6 m o nt h s  
1 2)  A f ail e d t h er a p e uti c tri al of e s cit al o pr a m i n t h e c urr e nt d e pr e s si v e e pi s o d e ( d efi n e d a s at l e a st 6 w e e k s 
of tr e at m e nt at a d ail y d o s e of 1 0 m g or hi g h er)  
1 3)  K n o w n all er g y or h y p er s e n siti vit y t o e s cit al o pr a m or b u pr o pi o n  
1 4)  C urr e nt or pl a n n e d p s y c h ot h er a p y  
 
W e will a d diti o n all y e nr oll u p t o 6 0 ol d er a d ult s wit h n o hi st or y of p s y c hi atri c or n e ur ol o gi c al ill n e s s i n or d er t o 
h a v e 4 0 s u bj e ct s wit h M RI d at a. D at a g at h er e d fr o m t hi s c o h ort will a s si st u s a s w e i nt er pr et d at a fr o m t h e 
d e pr e s s e d c o h o rt. E ntr y crit eri a will b e si mil ar t o t h o s e of t h e d e pr e s s e d c o h ort, b ut a dj u st e d t o r efl e ct w e w a nt 
t o e nr oll i n di vi d u al s wit h o ut a n y hi st or y of d e pr e s si o n or ot h er p s y c hi atri c ill n e s s. 
 
N o n d e pr e s s e d C o h ort:  
I n cl u si o n Crit eri a: 
1)  A g e 6 0 y e ar s or ol d er.  
2)  Mi ni -M e nt al St at e E x a m ≥ 2 4 . 
3)  A bilit y t o r e a d a n d writ e E n gli s h.  
4)  M A D R S s c or e <  8  
 
E x cl u si o n Crit eri a:  
Di a g n o sti c I s s u e s:  
1)  C urr e nt or p a st di a g n o s e s of a n y A xi s I p s y c hi atri c di s or d er s  
2)  A n y u s e of illi cit s u b st a n c e s ( s u c h a s m arij u a n a or c o c ai n e) or a b u s e of pr e s cri pti o n m e di c ati o n s ( s u c h 
a s b e n z o di a z e pi n e s or o pi at e s) wit hi n t h e l a st t hr e e m o nt h s.  
3)  Pr e s e n c e of a c ut e s ui ci d alit y  
4)  C urr e nt or p a st p s y c h o si s  
M e di c al I s s u e s:  
5)  K n o w n pri m ar y n e ur ol o gi c al di s or d er, i n cl u di n g d e m e nti a, br ai n t u m or s, e pil e p s y, P ar ki n s o n’ s di s e a s e, 
or d e m y eli n ati n g di s e a s e s  
6)  C hr o ni c u ntr e at e d m e di c al di s or d er s (i n cl u di n g b ut n ot li mit e d t o h y p ert e n si o n, h y p erli pi d e mi a, 
fi br o m y al gi a, h y p ot h yr oi di s m, or a n y m e di c al di s or d er) w h er e tr e at m e nt i s w arr a nt e d 
7)  A n y p h y si c al or i nt ell e ct u al di s a bilit y aff e cti n g c o m pl eti o n of a s s e s s m e nt s  
8)  M RI c o ntr ai n di c ati o n s  
A nti d e pr e s s a nt Tr e at m e nt I s s u e s:  
9)  A n y hi st or y of a nti d e pr e s s a nt tr e at m e nt, i n cl u di n g a nti d e pr e s s a nt m e di c ati o n s, p s y c h ot h er a p y, or br ai n 
sti m ul ati o n s u c h a s E C T. Bri ef c o u pl e s / m arti al c o u n s eli n g, w h er e t h e f o c u s of tr e at m e nt w a s n ot a 
p s y c hi atri c ill n e s s i s all o w a bl e.  
 
 
5. 0 E N R O L L M E N T A N D C O N S E N T  
W e will e nr oll p ati e nt s fr o m cli ni c al r ef err al s a n d r e s p o n s e t o a d v erti s e m e nt s.  I n t h e s e c a s e s, p ot e nti al 
p arti ci p a nt s will c all o ur st u d y c o nt a ct n u m b er.  W e will d e s cri b e t h e st u d y t o t h e m, i n cl u di n g a d e s cri pti o n of 
t h e st u d y e ntr y crit eri a.  T h o s e w h o c o nti n u e t o b e i nt er e st e d will t h e n b e s c h e d ul e d f or a n e v al u ati o n.  Aft er 
s c h e d uli n g, a st u d y d o ct or will r e vi e w t h eir el e ctr o ni c m e di c al r e c or d t o a s s ur e t h at p ot e nti al s u bj e ct s m e et 
e ntr y crit eri a, h o w e v er n o d at a will b e r e c or d e d.  O c c a si o n all y a cli ni ci a n m a y i d e ntif y a p ati e nt w h o m a y b e 


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eli gi bl e a n d r e q u e st t h at w e i niti at e c o nt a ct.  W e will d o t hi s, b ut t h e r ef erri n g cli ni ci a n m u st fir st br o a c h t h e i d e a 
of r e s e ar c h a n d s e c ur e t h e p ati e nt’ s a gr e e m e nt t o b e c o nt a ct e d.  
 
U p o n pr e s e nti n g f or e v al u ati o n, w e  will o bt ai n f or m al writt e n  c o n s e nt fr o m all p arti ci p a nt s .  F oll o wi n g 
p oli ci e s of t h e V a n d er bilt U ni v er sit y H e alt h S y st e m I n stit uti o n al R e vi e w B o ar d, writt e n i nf or m e d c o n s e nt will b e 
o bt ai n e d a n d d o c u m e nt e d b y t h e st u d y’ s R e s e ar c h C o or di n at or b ef or e a n y st u d y -r el at e d pr o c e d ur e s ar e 
p erf or m e d.  T h e  st u d y c o or di n at or will r e vi e w st u d y pr o c e d u r e s a n d t h e c o n s e nt f or m wit h e a c h p ot e nti al 
p arti ci p a nt.  A st u d y d o ct or  will b e a v ail a bl e s h o ul d a n y c o n s e nt -r el at e d q u e sti o n s ari s e.  E a c h i n di vi d u al m a y 
t a k e a s m u c h ti m e a s t h e y li k e t o d e ci d e if t h e y d o or d o n ot wi s h t o p arti ci p at e. 
 
W e will  all o w t h at n o n d e pr e s s e d p arti ci p a nt s c a n b e c o n s e nt e d a n d c o m pl et e t h e s cr e e ni n g vi sit wit h o ut 
c o mi n g p h y si c all y t o V U M C.  T hi s will b e c o n d u ct e d vi a HI P P A c o m pli a nt Z o o m t el e c o nf er e n ci n g u nl e s s t h e r e 
ar e t e c h ni c al pr o bl e m s wit h Z o o m, i n w hi c h c a s e w e wil l u s e F a c eti m e or ot h er vi d e o c o nf er e n ci n g s oft w ar e at 
t h e p arti ci p a nt’ s r e q u e st. A n e-c o n s e nt pr o c e s s will b e c o n d u ct e d u si n g a R E D C a p -b a s e d el e ctr o ni c c o n s e nt 
f or m. T h e c o n s e nt f or m h a s b e e n d e v el o p e d i n R E D C a p, a s e c ur e, w e b-b a s e d, HI P A A -c o m p li a nt, d at a 
c oll e cti o n pl atf or m  wit h a u s er m a n a g e m e nt s y st e m all o wi n g pr oj e ct o w n er s t o gr a nt a n d c o ntr ol v ar yi n g l e v el s 
of a c c e s s t o d at a c oll e cti o n i n str u m e nt s a n d d at a ( e. g. r e a d o nl y, d e -i d e ntifi e d-o nl y d at a vi e w s) f or ot h er u s er s.   
 
P ot e nti al p arti ci p a nt s will b e i niti all y e v al u at e d u si n g o ur c urr e ntl y t el e p h o n e s cr e e ni n g a p pr o a c h.  If 
t h e y a p p e ar eli gi bl e, t h e y will b e s c h e d ul e d f or a Z o o m m e eti n g.  O n c e t h at m e eti n g i s i niti ali z e d, t h e fir st st e p 
will b e t o o bt ai n e -C o n s e nt u si n g t h e R E D C a p s ur v e y vi a i P a d or ot h er p ort a bl e el e ctr o ni c d e vi c e.  T hi s li n k will 
b e e m ail e d t o t h e m.  A st u d y c o or di n at or will r e vi e w t h e c o n s e nt f or m w hil e t el e c o nf er e n ci n g wit h t h e 
p arti ci p a nt a n d a n s w er a n y q u e sti o n s b ef or e t h e p arti ci p a nt si g n s.  
 
P ati e nt si g n at ur e s will b e o bt ai n e d u si n g R E D C a p’ s ‘ Si g n at ur e’ fi el d t y p e o n t h e s ur v e y.  U p o n 
c o m pl eti o n of t h e c o n s e nt, p arti ci p a nt s will b e a bl e t o d o w nl o a d a si g n e d c o p y of t h e c o n s e nt f or m.  W e will 
al s o pr o vi d e t h e m wit h a c o p y of t h eir v er si o n of t h e c o n s e nt d o c u m e nt si g n e d b y t h e m a n d b y t h e c o n s e nti n g 
st u d y st aff m e m b er b y m aili n g of a h ar d c o p y of t h e c o n s e nt.  
 
T h e r e m ai n d er of t h e s cr e e ni n g vi sit will c o nti n u e a s d e s cri b e d b el o w a n d i n v ol v e a s s e s s m e nt s 
o bt ai n e d b y t h e st u d y c o or di n at or a n d a st u d y p h y si ci a n.  T h e o nl y diff er e n c e wi ll b e t h at t h e M M S E, t y pi c all y 
o bt ai n e d at t h e s cr e e ni n g vi sit, will i n st e a d b e o bt ai n e d at t h e b a s eli n e vi sit. N o n -d e pr e s s e d p arti ci p a nt s w h o 
c o m pl et e t h e s cr e e ni n g vi sit i n p er s o n will ot h er wi s e f oll o w t h e s cr e e ni n g vi sit pl a n d e s cri b e d b el o w.  
 
T hi s pr o c e s s will n ot b e u s e d f or p arti ci p a nt s e nr oll e d t hr o u g h T V H S.  
 
 
 
6. 0 E N R O L L M E N T  A N D C O N S E N T P R O C E S S E S  S P E CI FI C T O V A T E N N E S S E E V A L L E Y H E A L T H 
S Y S T E M ( T V H S)  
W e al s o a nti ci p at e e nr olli n g p ati e nt s fr o m t h e V A T V H S vi a cli ni c al r ef err al s a n d r e s p o n s e s t o a d v erti s e m e nt s.  
O nl y d e pr e s s e d p arti ci p a nt s will b e e nr oll e d fr o m t h e V A.  A s wit h o ur c urr e nt pl a n, w e will d e s cri b e t h e st u d y 
p ur p o s e a n d pr o c e d ur e s t o t h e m, i n cl u di n g a d e s cri pti o n of t h e st u d y e ntr y crit eri a.  T h o s e w h o c o nti n u e t o b e 
i nt er e st e d will b e s c h ed ul e d f or a n e v al u ati o n.  A st u d y d o ct or will r e vi e w t h eir el e ctr o ni c m e di c al r e c or d t o 
a s s ur e t h at p ot e nti al s u bj e ct s a p p e ar t o m e et e ntr y crit eri a, h o w e v er n o d at a will b e r e c or d e d.  O c c a si o n all y a 
cli ni ci a n m a y i d e ntif y a p ati e nt w h o i s p ot e nti all y eli g i bl e a n d r e q u e st t h at w e i niti at e c o nt a ct.  W e will d o t hi s, 
b ut t h e r ef erri n g cli ni ci a n m u st fir st br o a c h t h e i d e a of r e s e ar c h a n d s e c ur e t h e p ati e nt’ s a gr e e m e nt t o b e 
c o nt a ct e d.  
 
T h e i niti al e v al u ati o n a n d o bt ai ni n g writt e n i nf or m e d c o n s e nt will o c c ur at  V U M C. Inf or m e d c o n s e nt will 
b e o bt ai n e d a n d d o c u m e nt e d b y a st u d y d o ct or or t h e st u d y’ s R e s e ar c h C o or di n at or b ef or e a n y st u d y-r el at e d 
pr o c e d ur e s ar e p erf or m e d .  V et er a n s w h o r e c ei v e c ar e at t h e V A T V H S will b e a s k e d t o si g n b ot h t h e V U M C 
i nf or m e d c o n s e nt d o c u m e nt a s w ell a s a s e p ar at e V A T V H S i nf or m e d c o n s e nt d o c u m e nt.  
 
 
 
7. 0 . S T U D Y O V E R VI E W  
Aft er c o n s e nt, s u bj e ct s will b e e v al u at e d f or eli gi bilit y.  Aft er st a n d ar di z e d cli ni c al a n d c o g niti v e a s s e s s m e nt s 
a n d M RI, s u bj e ct s will b e gi n 8 -w e e k s of d o u bl e -bli n d e d st u d y dr u g, eit h er e s cit al o pr a m or pl a c e b o.  T h o s e w h o 
d o n ot r e mit, d efi n e d a s a M A D R S  ≤ 7 at t h e l a st a s s e s s m e nt, will e nt er a n 8 -w e e k o p e n -l a b el tri al of 
b u pr o pi o n X L. S u bj e ct s will b e e v al u at e d e v er y t w o w e e k s vi a m o nt hl y cli ni c vi sit s a n d t el e p h o n e vi sit s at 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
i nt er v e ni n g t w o w e e k s. 
 
N o n d e pr e s s e d p arti ci p a nt s will o nl y c o m pl et e t h e s cr e e ni n g a n d b a s eli n e a s s e s s m e nt s.  T h e y will n ot 
r e c ei v e st u d y m e di c ati o n or f oll o w-u p a s s e s s m e nt s.  
 
 
8. 0 S T U D Y A S S E S S M E N T S  
8. 1. Cli ni c al & C o g niti v e A s s e s s m e nt s: T h e s e ar e pri m aril y  d o n e at t h e s cr e e ni n g vi sit or t h e Bi o m ar k er / 
T e sti n g vi sit. M e a s ur e s of d e pr e s si o n s e v erit y, a d v er s e e v e nt s, a n d tr e at m e nt c o m pli a n c e o c c ur at all vi sit s.  
8. 1. a. Di a g n o s e s a n d S y m pt o m S e v erit y : C urr e nt a n d p a st p s y c hi atri c di a g n o s e s will b e a s s e s s e d u si n g t h e 
el e ctr o ni c v er si o n of t h e v ali d at e d Mi ni -I nt er n ati o n al N e ur o p s y c hi atri c I nt er vi e w Pl u s (MI NI + ) (9 9 ,1 0 0 ) & 
c o nfir m e d t hr o u g h a cli ni c al i nt er vi e w w hi c h will a s s e s s a g e of i niti al o n s et .  D e pr e s si o n s e v erit y  
will b e a s s e s s e d u si n g t h e M A D R S  (1 0 1 ) a s o ur pri m ar y o ut c o m e  m e a s ur e, wit h a n a pri ori  d efi niti o n of 
r e mi s si o n b ei n g M A D R S ≤ 7 at t h e la st a s s e s s m e nt.  T h e QI D S -S R 1 6  (1 0 2 -1 0 4 ) i s a s e c o n d ar y d e pr e s si o n  
s e v erit y m e a s ur e, i n cl u d e d a s s elf -r e p ort s c al e s ar e l e s s s u s c e pti bl e t o cli ni ci a n bi a s.  T h e s e m e a s ur e s will b e 
c oll e ct e d e v er y t w o w e e k s.  T h o u g ht s of s ui ci d e will b e a s s e s s e d at st u d y e ntr y b y t h e st u d y p h y si ci a n u si n g 
t h e C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e ( C-S S R S).  S af et y a n d  t h e pr e s e n c e of s ui ci d al i d e ati o n will b e 
a s s e s s e d at e v er y c o nt a ct .   
Pri or e x p o s ur e t o a nti d e pr e s s a nt s will b e a s s e s s e d wit h a m o difi e d v er si o n of t h e A nti d e pr e s s a nt 
Tr e at m e nt Hi st or y F or m ( A T H F; A p p e n di x  3 ) (1 0 5 ,1 0 6 ).  W e will u s e a n u p d at e d v er si o n i n cl u di n g c urr e nt 
a nti d e pr e s s a nt s a n d a nti p s y c h oti c s a p pr o v e d f or M D D.  W e will r e q u e st m e di c al r e c or d s a s n e e d e d.  
 A p at h y i s a s s e s s e d wit h t h e A p at h y E v al u ati o n S c al e (1 0 7 ).  T hi s v ali d s c al e u s e s  m e a s ur e s di sti n ct 
fr o m d e pr e s si v e s y m pt o m s (1 0 7 ,1 0 8 ). C hil d h o o d tr a u m a hi st or y will b e a s s e s s e d u si n g t h e C hil d h o o d Tr a u m a 
Q u e sti o n n air e ( C T Q).  
8. 1 . b. M e di c al : All m e di c al c o m or bi diti e s  will b e q u a ntifi e d u si n g t h e C u m ul ati v e Ill n e s s R ati n g S c al e  (CI R S ) 
(1 0 9 ), w hi c h c o v er s all m aj or s y st e m s a n d pr o vi d e s a co m p o sit e m e di c al m or bi dit y s c or e.  V a s c ul ar ri s k will b e 
s p e cifi c all y m e a s ur e d a n d a s s e s s e d  t hr o u g h t h e Fr a mi n g h a m Str o k e Ri s k  ( A p p e n di x 4) (1 1 0 ).  F or s af et y, 
c o n c o mit a nt m e di c ati o n s a n d vit al si g n s ( bl o o d pr e s s ur e, p ul s e) will b e r e vi e w e d at e a c h vi sit.   Di s a bilit y will b e 
a s s e s s e d u si n g t h e W H O -D A S 2. 0.  
 
T o a s s ur e s af et y f or M RI, w e c ar ef ull y s cr e e n p arti ci p a nt s f or m et al.  W or ki n g wit h t h e V a n d er bilt 
U ni v er sit y I n stit ut e f or I m a gi n g S ci e n c e, w e i d e ntif y p a st m e di c al pr o c e d ur e s a n d s ur g eri e s t h at m a y i n cl u d e 
m et al i m pl a nt s.  I n t h e s e c a s e s, w e r e q u e st m e di c al r e c or d s t o d et er mi n e if m et al w a s u s e d, a n d if s o, if it i s 
s af e f or 3 T e sl a M RI.  H o w e v er, i n s o m e c a s e s t h e s e r e c or d s c a n n ot b e o bt ai n e d.  I n s u c h c a s e s w e m a y 
o bt ai n a n x -r a y if t h er e w a s a q u e sti o n w h et h er t h er e w a s or w a s n ot i m pl a nt e d m et al. 
W e will o nl y o bt ai n a n x -r a y i n c a s e s w h er e a) t h er e i s a s af et y c o n c er n a b o ut a p ot e nti al i m pl a nt or 
m et al; b) m e di c al r e c or d s f or t h e s ur g er y ar e n ot a v ail a bl e; a n d c) p ar ti ci p a nt s d o n ot t hi n k t h at m et al w a s 
i n v ol v e d i n t h e s ur g er y.  T h u s t hi s pr o c e d ur e will n ot b e n e e d e d f or t h e m aj orit y of p arti ci p a nt s.  If t h e x-r a y 
s h o w s t h er e i s i m pl a nt e d m et al t h at c o ul d b e a M RI c o ntr ai n di c ati o n, t h at p arti ci p a nt will b e wit h dr a w n f r o m t h e 
st u d y.   R a di ati o n e x p o s ur e will v ar y d e p e n d e nt o n t h e ar e a n e e di n g t o b e e v al u at e d.  
B a s e d o n r e c o m m e n d ati o n s fr o m NI H, w e f or m all y e x cl u d e f or c urr e nt pr e g n a n c y.  Gi v e n t h e st u d y’ s 
mi ni m u m eli gi bl e a g e i s 6 0 y e ar s, w e a nti ci p at e all  f e m al e p arti ci pa nt s will b e p o st m e n o p a u s al  ( G ol d E B, et al.  
A m J E pi d e mi ol, 1 5 3: 8 6 5 -8 7 4, 2 0 0 1) .  T o a d dr e s s t hi s c o n c er n, w e will a s k a b o ut t h e p ot e nti al f or pr e g n a n c y 
a n d ti m e si n c e t h e l a st m e n str u al p eri o d . If a w o m a n pr e s e nt s w h o i s c a p a bl e of h a vi n g c hil dr e n (i. e., h a s n ot   
h a d a h y st er e ct o m y or bil at er al o o p h or e ct o m y) a n d i s n ot cl e arl y p o st m e n o p a u s al ( d efi n e d a s > 1 y e ar of 
a m e n orr h e a), w e will d et er mi n e s h e i s i n eli gi bl e a n d n ot e nr oll h er i n t h e st u d y.  W e t a k e t hi s r o ut e o v er 
r e q uiri n g u s e of c o ntr a c e pti o n f or s af et y r e a s o n s, gi v e n t h e ri s k s of l o n g-t er m u s e of h or m o n al tr e at m e nt s i n 
ol d er w o m e n.  
8. 1 . c. Si d e Eff e ct s / Tr e at m e nt C o m pli a n c e : Si d e eff e ct s will b e a s s e s s e d u si n g t h e Fr e q u e n c y a n d I nt e n sit y  
of Si d e Eff e ct s R ati n g / Gl o b al R ati n g of Si d e Eff e ct B ur d e n ( FI S E R/ G R S E B ) s c al e (1 1 1 ).  C o m pli a n c e will b e 
a s s e s s e d wit h  a pill c o u nt a n d t h e M e di c ati o n A d h er e n c e Q u e sti o n n air e (M A Q ) (1 1 2 ). 
8 . 1. d. Ot h er P h e n ot y pi c A s s e s s m e nt s: W e will m o v e b e y o n d tr a diti o n al di a g n o sti c crit eri a f or a br o a d er 
e x a mi n ati o n of s p e cifi c d e pr e s si v e s y m pt o m s. T h e f oll o wi n g a s s e s s m e nt s will b e a d mi ni st er e d at eit h er t h e 
s cr e e ni n g  or b a s eli n e  vi sit, t h e n a g ai n aft er c o m pl eti n g e a c h 8 -w e e k st u d y dr u g p h a s e: I n s o m ni a S e v erit y 
I n d e x (I SI), R u mi n ati v e R e s p o n s e S c al e ( R R S), P e n n St at e W orr y Q u e sti o n n air e ( P S W Q), F ati g u e S e v erit y 
S c al e ( F S S), a n d t h e S n ait h -H a milt o n Pl e a s ur e S c al e ( S H A P S) , t h e P R O MI S A p pli e d C o g niti o n A biliti e s S h ort 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
F or m, t h e T y p e D S c al e ( D S -1 4) of n e g ati v e aff e ct, t h e G e n er ali z e d A n xi et y Di s or d er 7 it e m s c al e ( G A D 7) a n d 
t h e Att e nti o n al C o ntr ol S c al e. Al s o, t h e P er c ei v e d Str e s s S c al e ( P S S) a n d t h e P er c ei v e d S o ci al 
S u p p ort/ C o nfli ct s ur v e y will b e a d mi ni st er e d at t h e b a s eli n e vi sit.  
 
 
8. 2 . C o g niti v e A s s e s s m e nts : S u bj e ct s ar e e x cl u d e d f or 
M M S E s c or e s < 2 4 or  a di a g n o si s of d e m e nti a.  
O ur c o g niti v e  d o m ai n a s s e s s m e nt a p pr o a c h ( T a bl e 1 ) i s 
p u bli s h e d (2 1 ,1 1 3 ). W e gr o u p t h e c o g niti v e t a s k s i nt o r ati o n all y 
m oti v at e d d o m ai n s wit h  r e a s o n a bl e i nt er n al co n si st e n c y b y 
Cr o n b a c h’ s al p h a. W e  will cr e at e Z -s c or e s f or e a c h t a s k 
m e a s ur e a cr o s s p arti ci p a nt s a n d t o cr e at e t h e d o m ai n s c or e, 
s u m t h e Z -s c or e s  of t h e t a s k s i n t h at d o m ai n .  V ari a bl e s i n 
w hi c h g o o d p erf or m a n c e i s r e pr e s e nt e d b y l o w er v al u e s r at h er 
t h a n hi g h er v al u e s will b e r e v er s e s c or e d s o  hi g h er Z -s c or e s 
r e pr e s e nt b ett er p erf or m a n c e f or all v ari a bl e s.  T hi s b att er y 
c o v er s  t h e r a n g e of c o g niti v e d efi cit s a s s o ci at e d wit h p o or 
a nti d e pr e s s a nt r e s p o n s e  i n L L D (2 1 ,5 7 ,1 1 4 ).  
 U si n g Z -s c or e s i n cr e a s e s p o w er b ut d e cr e a s e s s e n siti vit y.  
O ur pri m ar y c o g niti v e o ut c o m e s will b e t h e d o m ai n s c or e s, b ut 
t o i m pr o v e s e n siti vit y w e will al s o e x a mi n e p erf or m a n c e o n 
i n di vi d u al m e a s ur e s, p arti c ul arl y f or E x pl or at or y Ai m 1. 
 
9 .0.  R A N D O MI Z A TI O N & S T U D Y D R U G A D MI NI S T R A TI O N  
9. 1 . R a n d o mi z ati o n: Aft er i niti al a s s e s s m e nt s, p arti ci p a nt s ar e r a n d o mi z e d t o d o u bl e -bli n d e d P h a s e 1 dr u g 
a s si g n m e nt ( e s cit al o pr a m or pl a c e b o).  A s o ur pri m ar y i nt er e st f or P h a s e 1 i s r el at e d t o e s cit al o pr a m r e s p o n s e, 
w e will all o c at e p arti ci p a nt s i n a 2: 1 dr u g -t o-pl a c e b o r ati o.  R a n d o mi z ati o n will b e c o n d u ct e d b y t h e V a n d er bilt 
I n v e sti g ati o n al Dr u g S er vi c e. N o n d e pr e s s e d i n di vi d u al s will n ot b e r a n d o mi z e d t o st u d y dr u g. 
R a n d o mi z ati o n will b e str atifi e d b y M RI m e a s ur e s  of t ot al c er e br al W M L v ol u m e .  O ur m e a s ur e m e nt 
of t ot al W M L v ol u m e i s a ut o m at e d a n d a v ail a bl e wit hi n 2 4 h o ur s of t h e s c a n a n d s u bj e ct s will b e str atifi e d a s 
“ hi g h” or “l o w” t ot al c er e br al W M L v ol u m e.  B a s e d o n pil ot d at a, w e will u s e a c ut off of 3. 8 6 m L ; t hi s i s t he 
m e di a n 3 T W M L v ol u m e fr o m a c o h ort of 1 4 5 d e pr e s s e d el d er s a n al y z e d u si n g o ur W M L s e g m e nt ati o n 
m et h o d.  W h e n w e r e a c h 5 0 % e nr oll m e nt, w e will r e -a s s e s s t hi s c ut off b a s e d o n st u d y d at a a n d a dj u st if 
n e c e s s ar y.   
If t h er e ar e d el a y s i n s c a n pr o c e s si n g, stratifi c ati o n will b e d et er mi n e d u si n g t h e C off e y -m o difi e d F a z e k a s 
vi s u al r ati n g s c al e (2 ), di c h ot o mi zi n g p arti ci p a nt s a s “ hi g h” ( 2 or 3, c o nfl u e n c e of f o ci) or “l o w” ( 0 or 1, a b s e nt or 
p u n ct at e f o ci).   
M RI m e a s ur e s will o nl y b e u s e d f or str atifi c ati o n.  T h e y will n ot g ui d e or d et er mi n e tr e at m e nt d e ci si o n s.  
9. 2. P h a s e 1: Bli n d e d E s cit al o pr a m  or Pl a c e b o : W e s el e ct e d e s cit al o pr a m  d u e t o it s t ol er a bilit y , e a s e of 
d o si n g, a n d l a c k of eff e ct s o n d o p a mi n e a n d n or e pi n e p hri n e (1 1 5 ). T h e V a n d er bilt I D S will pr e p ar e o v er -
e n c a p s ul at e d e s cit al o pr a m a n d m at c hi n g pl a c e b o a n d m ai nt ai n t h e bli n d e d a s si g n m e nt i n c a s e of 
e m er g e n ci e s.  P arti ci p a nt s will r e c ei v e o n e t a bl et ( 1 0 m g or pl a c e b o) f or at l e a st 2 w e e k s.  If t ol er at e d, it c a n b e 
i n cr e a s e d t o a tar g et d o s e of t w o t a bl et s ( 2 0 m g) d ail y at t h e t w o -w e e k st u d y c o nt a ct, b ut d o si n g c h a n g e s will 
n ot b e m a d e at w e e k 6 or l at er.  F or  pr o bl e m s wit h t ol er a bilit y, t h e d o s e c a n b e r e d u c e d t o th e pr e vi o u s l e v el, 
b ut n ot b el o w o n e t a bl et d ail y.  
9. 3 . Tr a n siti o n: Aft er 8 w e e k s s u bj e ct s will b e a s s e s s e d f or r e mi s si o n ( M A D R S ≤ 7).  T h o s e a c hi e vi n g 
r e mi s si o n will e n d t h eir st u d y p arti ci p ati o n.  T h o s e w h o ar e n ot r e mitt e d will h a v e t h eir P h a s e 1 dr u g t a p er e d 
o v er a w e e k t o d e cr e a s e t h e c h a n c e of di s c o nti n u ati o n s y n dr o m e  t h e n pr o gr e s s t o P h a s e 2. 
9 . 4. P h a s e 2 : B u pr o pi o n X L: W e s el e ct e d b u pr o pi o n d u e t o it s di sti n ct m e c h a ni s m of a cti o n: a n or e pi n e p hri n e 
/ d o p a mi n e r e u pt a k e i n hi bit or wit h n o eff e ct o n s er ot o ni n (1 1 6 ,1 1 7 ). B u pr o pi o n i s s af e a n d eff e cti v e i n el d erl y 
p o p ul ati o n s (1 1 8 -1 2 0 ).  S u bj e ct s will r e c ei v e o p e n -l a b el b u pr o pi o n X L st arti n g at 1 5 0 m g d ail y.  If t ol er at e d, 
aft er 1 -2 w e e k s it will b e i n cr e a s e d t o 3 0 0 m g d ail y.  T h e d o s e m a y b e f urt h er i n cr e a s e d t o t h e m a xi m u m of 
4 5 0 m g d ail y at w e e k 4; t hi s d o s e will b e r e d u c e d if n e e d e d f or t ol er a bilit y. S u bj e ct s n ot t ol er ati n g t h e 3 0 0 m g 
d o s e will b e wit h dr a w n.   
T a bl e 1 . C o g niti v e D o m ai n s & T a s k s (2 1 ) 
E pi s o di c M e m or y ( Al p h a = 0. 7 6)  
•  W or d Li st r e c all; L o gi c al m e m or y; 
C o n str u cti o n al pr a xi s; B e nt o n Vi s u al 
R et e nti o n T e st  
E x e c uti v e F u n cti o n ( Al p h a = 0. 7 3)  
•  V er b al Fl u e n c y; Tr ail M a ki n g T e st, P art 
B; Str o o p, c ol or -w or d i nt erf er e n c e; 
M atti s D R S, I niti ati o n -P er s e v er ati o n 
s u b s c al e; Wi s c o n si n C ar d S orti n g T e st  
L a n g u a g e Pr o c e s si n g ( Al p h a = 0. 6 2)  
•  S hi pl e y V o c a b ul ar y T e st; B o st o n 
N a mi n g T e st; Str o o p, w or d r e a di n g 
Pr o c e s si n g S p e e d ( Al p h a = 0. 6 9)  
•  S y m b ol -di git M o d alit y T e st; Str o o p, 
c ol or n a mi n g; Tr ail M a ki n g T e st, P art A  
W or ki n g M e m or y ( Al p h a = 0. 6 8)  
•  Di git S p a n, f or w ar d; Di git S p a n, 
b a c k w ar d s; A s c e n di n g Di git s  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
Alt h o u g h b u pr o pi o n i s oft e n u s e d f or a u g m e nt ati o n (1 2 1 -1 2 3 ) f or P h a s e 2 w e d e ci d e d t o u s e it a s 
m o n ot h er a p y .  T hi s i s s u p p ort e d b y S T A R* D d at a (1 2 4 ) t h at f o u n d n o cl e ar pr ef er e n c e f or a u g m e nt ati o n 
v er s u s s wit c h str at e gi e s (1 2 5 ).  T hi s will si m plif y i nt er pr et ati o n of Ai m 2 d at a. 
B u pr o pi o n x l m a y b e o bt ai n e d t hr o u g h t h e V a n d er bilt i n v e sti g ati o n al p h ar m a c y a n d pr o vi d e d t o s u bj e ct s.  
Alt er n ati v el y, t h e st u d y d o ct or will pr o vi d e a pr e s cri pti o n a n d t h e y m a y o bt ai n it t hr o u g h t h eir r e g ul ar p h ar m a c y.  
I n t hi s c a s e, t h e y will b e i n str u ct e d t o s a v e th eir r e c ei pt s s o t h e y c a n b e r ei m b ur s e d f or t h eir c o st.  
9. 5 . E n d of st u d y m e di c ati o n pr o c e d ur e s: F or s u bj e ct s w h o wi s h t o c o nti n u e o n t h eir e n d-of -st u d y dr u g, w e 
will pr o vi d e pr e s cri pti o n s a n d a s si st wit h f oll o w -u p.  If t h e y d o n ot wi s h t o c o nti n u e o n st u d y dr u g, w e will m a k e 
r ef err al s a n d w or k wit h t h at pr o vi d er t o s af el y t a p er t h e st u d y dr u g.  S e e H u m a n S u bj e ct s  f or m or e d et ail. 
9. 6 . C o n c o mit a nt tr e at m e nt: T o e n h a n c e g e n er ali z a bilit y, m o st n o n p s y c h otr o pi c m e di c ati o n s will b e 
p er mitt e d . C o n c o mit a nt p s y c h ot h er a p y will n ot b e all o w e d a s it i s a n eff e cti v e tr e at m e nt t h at c o ntri b ut es  t o 
r e mi s si on t hr o u g h diff er e nt m e c h a ni s m s .  W e all o w s h ort -a cti n g h y p n oti c s ( e s z o pi ci o n e , z ol pi d e m, or z al e pl o n)  
f or sl e e p a n d l or a z e p a m u p t o 2 m g d ail y f or a n xi et y.  H y p n oti c s will b e di s c o ur a g e d t h e d a y of c o g niti v e t e sti n g. 
9 . 7 A nti d e pr e s s a nt W a s h o ut:  If p ot e nti al s u bj e ct s ar e c urr e ntl y t a ki n g a n a nti d e pr e s s a nt, t h e y m a y n e e d t o 
c o m e off t h at a nti d e pr e s s a nt i n or d er t o p arti ci p at e.  I n or d er t o q u alif y t o h a v e t h e c urr e nt a nti d e pr e s s a nt 
st o p p e d, p arti ci p a nt s will n e e d t o h a v e c o nti n u e d si g nifi c a nt d e pr e s si v e s y m pt o m at ol o g y ( M A D R S > = 1 5) 
d e s pit e t a ki n g a t h er a p e uti c  d o s e of t h eir c urr e nt a nti d e pr e s s a nt f or at l e a st 6 w e e k s. T h e t h er a p e uti c d o s e wi ll 
b e dr u g s p e cifi c, b ut  e q ui v al e nt t o fl u o x eti n e 2 0 m g ( s u c h a s s ertr ali n e 5 0 m g or e s cit al o pr a m 1 0 m g, f or 
e x a m pl e). I n di vi d u al s w h o r e s p o n d e d t o t h eir a nti d e pr e s s a nt a n d d o n ot h a v e t hi s l e v el of d e pr e s si v e s y m pt o m 
s e v erit y will n ot  b e e nr oll e d i n t h e st u d y a n d will n ot  b e t a p er e d off t h eir m e di c ati o n.  T h e m e di c ati o n t a p er will 
o c c ur o v er 1 -3 w e e k s, d e p e n d e nt o n t h e dr u g, d o s e, a n d d ur ati o n.  T h e y will b e a s s e s s e d wit h w e e kl y 
t el e p h o n e vi sit s d uri n g t hi s p eri o d t o m o nit or f or d e pr e s si o n w or s e ni n g.   
9. 8.  S o ur c e of St u d y Dr u g : T h e V a n d er bilt I n v e sti g ati o n al Dr u g S er vi c e will pr o vi d e st u d y dr u g f or b ot h 
P h a s e 1 a n d P h a s e 2 f or all p arti ci p a nt s a si d e fr o m V et er a n s w h o r e c ei v e c ar e at t h e V A T V H S.  V et er a n s will 
r e c ei v e st u d y dr u g fr o m t h e V A T V H S R e s e ar c h P h ar m a c y.  T h e V a n d er bilt I D S will c o or di n at e wit h t h e V A 
T V H S R e s e ar c h P h ar m a c y t o a s s ur e a c c ur a c y i n st u d y dr u g a s si g n m e nt f or P h a s e 1.  
 
 
 
1 0 . 0 C L O S E D - L O N G -T E R M F O L L O W U P  ( S U B-S T U D Y)  
T h e l o n g -t er m f oll o w-u p s u b st u d y i s n o w cl o s e d. D e pr e s s e d i n di vi d u al s w h o w er e  r a n d o mi z e d w er e  a s k e d t o 
e nt er l o n g -t er m f oll o w-u p o v er t h e n e xt y e ar.  T hi s i n cl u d e d  o nl y mi ni m al -ri s k i nt er vi e w s a n d q u e sti o n n air e s 
o c c urri n g 6 -m o nt h s a n d 1 2 -m o nt h s aft er st u d y e xit.  T hi s di d  n ot aff e ct cli ni c al tr e at m e nt d e ci si o n s o v er t hi s 
p eri o d.  T h e g o al of t hi s e x pl or at or y s u b -st u d y w a s  t o g at h er d at a o n l o n g-t er m r at e s of d e pr e s si o n r el a p s e.  
W e e x a mi n e d  w h et h er n e ur oi m a gi n g m e a s ur e s o bt ai n e d at b a s eli n e or cli ni c al m e a s ur e s o bt ai n e d t hr o u g h o ut 
t h e st u d y ar e r el at e d t o s u b s e q u e nt r at e s of r el a p s e o v er t h e o n e-y e ar f oll o w -u p p eri o d.  
 
1 0 . 1. C o n s e nt: W e di s c u s s e d  t hi s o pti o n al s u b-st u d y at t h eir fi n al st u d y vi sit.  T h o s e w h o w er e  a gr e e a bl e w er e  
a s k e d t o si g n a s e p ar at e s u b -st u d y c o n s e nt f or m.  
1 0 . 2.  Pr o c e d ur e s:  T hi s o nl y i n v ol v ed  a t el e p h o n e i nt er vi e w a n d c o m pl eti o n of st u d y q u e sti o n n air e s at 6 - a n d 
1 2 -m o nt h s aft er st u d y c o m pl eti o n.  T h e t el e p h o n e i nt er vi e w i n cl u d e d  a n a s s e s s m e nt of c urr e nt  
m e di c ati o n u s e wit h t h e A T H F a n d d e pr e s si o n s e v erit y u si n g t h e M A D R S.  D uri n g t h e i nt er vi e w w e w or k e d t o 
i d e ntif y t h e d ur ati o n of ti m e t h e y e x p eri e n c e d cli ni c all y si g nifi c a nt d e pr e s si v e s y m pt o m s o v er t h e i nt eri m, 
p arti c ul arl y f or t h o s e i n di vi d u al s w h o r e mitt e d t hr o u g h t h e st u d y b ut l at er e x p eri e n c e d a r el a p s e of d e pr e s si o n.  
T h e t el e p h o n e i nt er vi e w w a s  f oll o w e d b y a c o m pl eti o n of st u d y q u e sti o n n air e s a s s e s si n g d e pr e s si v e 
s y m pt o m s –  t h e s e ar e li st e d i n S e cti o n 7. 1. d a b o v e. 
1 0 . 3. S af et y:   F or a n y p arti ci p a nt s w h o ar e d e pr e s s e d at eit h er a s s e s s m e nt, w e a s s ur ed  t h at t h e y w er e  
c urr e ntl y r e c ei vi n g tr e at m e nt f or t h eir d e pr e s si o n.  If s o, w e e n c o ur a g e d  t h e m t o l et t h eir p h y si ci a n k n o w a b o ut 
t h eir s y m pt o m s.  If t h e y w er e  n ot, w e pr o vi d e d  r ef err al r e c o m m e n d ati o n s, i n cl u di n g a r ef err al t o t h e V a n d er bilt 
P s y c hi atr y O ut p ati e nt Cli ni c s.  A s w e m a k e t h e s e r ef err al s at t h e e n d of t h e m ai n st u d y, w e d i d n ot a nti ci p at e 
t h at m a n y i n di vi d u al s will b e wit h o ut tr e at m e nt.   
 
W e al s o a s s e s s e d  f or t h o u g ht s of d e at h or s ui ci d e a s p art of m e a s uri n g d e pr e s si o n s e v erit y wit h t h e 
M A D R S.  A st u d y p h y si ci a n t h e n a s s e s s e d  t h e s af et y of a n y o n e e n d or si n g t h e s e t h o u g ht s a n d a cte d a s w a s  
cli ni c all y i n di c at e d.  T hi s m a y  h a v e  i n cl u d ed  f e e d b a c k t o t h e p ati e nt’ s tr e ati n g p s y c hi atri st or r ef err al s t o 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
i nt e n si v e o ut p ati e nt or i n p ati e nt h o s pit ali z ati o n.  
 
1 1 .0.  M RI P R O C E D U R E S  
1 1 .1 . I m a g e A c q ui siti o n: W e will i m a g e s u bj e ct s o n a 3 T P hili p s A c hi e v a s y st e m  u si n g a pr ot o c ol t h at 
a c q uir e s : A) d at a t o all o w a ut o m at e d ti s s u e i d e ntifi c ati o n ; B) diff u si o n w ei g ht e d d at a ; a n d C) B O L D d at a at r e st 
a n d d uri n g t h e e m oti o n al d ot -pr o b e t a s k . T h e pr ot o c ol will a c q uir e T 1 -w ei g ht e d ( 6 mi n), fl ui d-att e n u at e d 
i n v er si o n r e c o v er y ( F L AI R; 9 mi n), a n d diff u si o n -w ei g ht e d  i m a g e s ( 9 mi n). W e will a s s e s s i n tri n si c F C ( 7. 5 mi n, 
7 7 0 0 t ot al fr a m e s)  w hil e  p arti ci p a nt s f o c u s o n a fi x at e d cr o s s. S u bj e ct s will t h e n c o m pl et e t h e e m oti o n al d ot -
pr o b e t a s k ( 3 0 mi n; S e ct. C. 9.f).  T h e s e s e q u e n c e s t all y a p pr o xi m at el y 6 0 mi n ut e s; w e b u d g et f or a 9 0 -mi n 
M RI t o all o w f or t h e l o n g er ti m e n e e d e d t o p o siti o n ol d er a d ult s a n d t o all o w a bri ef br e a k b et w e e n s e q u e n c e s 
if n e e d e d. 
1 1 . 2 F u n cti o n al M RI T a s k: T h e e m o tio n al pi ct ur e s d ot -pr o b e t a s k i s a c o m p ut eri z e d s p ati all y ori e nt e d 
a tte n tio n t a s k. T h e d ot pr o b e t a s k c o nt ai n s i m a g e s t a k e n fr o m t h e I nt er n ati o n al Aff e c tiv e Pi ct ur e S y st e m 
(I A P S)-i n cl u di n g n e utr al, p o sitiv e, a n d n e g a tiv el y v al e n c e d i m a g e s - a n d w a s d e v el o p e d t o m e a s ur e a tte n tio n al 
bi a s t o w ar d e m o tio n al i nf or m a tio n. I n t hi s t a s k t h e s u bj e ct i s pr e s e nt e d wit h p air s of pi ct ur e s pr e s e nt e d o n t h e 
l eft a n d ri g ht of t h e s cr e e n. F oll o wi n g a pi ct ur e p air pr e s e nt a tio n a n a st eri s k a p p e ar s o n eit h er t h e ri g ht or l e ft 
of t h e s cr e e n. T h e s u bj e ct i s i n str u ct e d t o i n di c at e t h e si d e of t h e s cr e e n o n w hi c h t h e a st eri s k a p p e ar s vi a 
b u tto n pr e s s, a s q ui c kl y a s p o s si bl e. T h e tim e b et w e e n w h e n t h e pr o b e a p p e ar s a n d w h e n t h e s u bj e ct pr e s s e s 
t h e c orr e s p o n di n g k e y t o it s l o c atio n i s r e c or d e d i n milli s e c o n d s a n d u s e d f or t h e c al c ul a tio n of f a cilit a tio n 
i n di c e s. T h e pri m ar y s c or e fr o m t h e t a s k i s a n atte n tio n al f a cilit a tio n i n d e x t h at i s c al c ul at e d s e p ar at el y f or t h e 
sli d e s of diff er e n t e m otio n al v al e n c e. F or t h e n e g a tiv e f a cilit a tio n i n d e x, it i s c al c ul at e d u si n g t h e f oll o wi n g 
f or m ul a: F a cilit atio n = 1/ 2 x [( N e utr al O nl y/ Pr o b e U p –  N e g a tiv e U p/ Pr o b e U p) + ( N e utr al O nl y/ Pr o b e D o w n –  
N e g a tiv e D o w n/ Pr o b e D o w n)]. T h u s, t hi s i n d e x i s c al c ul at e d b y s u btr a c tin g t h e p ar tici p a nt’ s a v er a g e r e s p o n s e 
tim e t o pr o b e s r e pl a ci n g n e g a tiv e s tim uli fr o m t h eir a v er a g e r e s p o n s e tim e t o pr o b e s r e pl a ci n g n e utr al s tim uli i n 
t h e v ari o u s n e utr al-n e utr al pi ct ur e p airi n g s. T hi s f or m ul a c o ntr ol s f or p ot e n tial  l o c atio n eff e ct s ( p ar tici p a nt’ s 
t e n d e n c y t o atte n d t o eit h er t h e ri g ht or l e ft l o c atio n of t h e s cr e e n) b y s u m mi n g l at e n ci e s f or l e ft a n d ri g ht 
pi ct ur e l o c a tio n s a n d t a ki n g t h eir a v er a g e. T h e f a cilit a tio n i n d e x f or p o si tiv e e m o tio n sli d e s i s c al c ul at e d i n t h e 
s a m e w a y. If t h e s p a tial l o c a tio n of t h e pr o b e c orr e s p o n d s t o t h e s a m e s p a tial l o c a tio n w h er e t h e p ar tici p a nt’ s 
a tte n tio n i s all o c at e d t h e n t h eir r e s p o n s e t o t h e pr o b e s’ l o c a tio n will b e f a st er.  
1 1. 3 . I m a g e Pr o c e s si n g: W M L S e g m e nt ati o n :  W M L i d e ntifi c ati o n a n d m e a s ur e m e nt will b e d o n e u si n g t h e 
L e si o n S e g m e nt ati o n T o ol b o x  (1 2 6 ), i m pl e m e nt e d t hr o u g h t h e V B M 8 t o ol b o x i n S P M 8. I n n ati v e s p a c e, e a c h 
v o x el o n t h e T 1 i m a g e i s a s si g n e d a s gr a y m att er, w hit e m att er, or C S F.  Aft er bi a s -c orr e cti o n t h e F L AI R i s 
c or e gi st er e d t o t h e T 1 i m a g e.  T h e t o ol b o x i niti all y cr e at e s a c o n s er v ati v e bi n ar y W M L m a p b a s e d o n o utli er 
v al u e s a cr o s s t h e T 1 a n d F L AI R i m a g e s.  N e xt, a l e si o n -gr o wt h al g orit h m u si n g M ar k o v R a n d o m Fi el d s 
m o d eli n g e xt e n d s t hi s c o n s er v ati v e m a p t o d efi n e t h e e xt e nt of t h e l e si o n s.  T hi s l e si o n m a p c a n t h e n b e 
n or m ali z e d i nt o st u d y -s p e cifi c s p a c e a n d u s e d t o c al c ul at e t ot al c er e br al W M L v ol u m e.  T hi s pr o c e s s t a k e s 
a p pr o xi m at el y 4 h o ur s fr o m t h e ti m e t h e i m a g e s ar e a c q uir e d fr o m t h e s c a n n er.  
 
1 1. 4  R e p e at M RI  ( S U B S T U D Y) 
 
A s a n  o pti o n al pr o c e d ur e, w e will a s k r a n d o mi z e d d e pr e s s e d p arti ci p a nt s t o h a v e a r e p e at M RI aft er 
c o m pl eti n g St u d y P h a s e 1 (t h e 8 -w e e k bli n d e d, pl a c e b o -c o ntr oll e d e s cit al o pr a m p h a s e).  M RI pr o c e d ur e s will 
b e t h e s a m e a s i n t h e b a s eli n e a s s e s s m e nt.  W e will a s k  p arti ci p a nt s a b o ut p arti ci p ati n g d uri n g e nr oll m e nt 
h o w e v er t h e y m a y c h a n g e t h eir mi n d at a n y p oi nt d uri n g st u d y p arti ci p ati o n.  T hi s a d d s n o a d diti o n al ri s k s t o 
t h e pr oj e ct. 
 
W hil e t h e p ur p o s e of t h e o v er all st u d y i s t o e x a mi n e h o w i m a gi n g m a y s er v e a s a pr e di ct or of a nti d e pr e s s a nt 
r e s p o n s e, t h e o v er all Ai m of t h e s u b st u d y i s t o e x a mi n e h o w n e ur al n et w or k c o n n e cti vit y c h a n g e s d uri n g t h e 
c o ur s e of t h e 8 -w e e k tri al.  W e h y p ot h e si z e w e will o b s er v e diff er e n c e s b et w e e n i n di vi d u al s w h o d o a n d d o n ot 
r e mit d uri ng P h a s e 1, w h er ei n i n di vi d u al s w h o r e mit will e x hi bit p o st -tr e at m e nt n et w or k c o n n e cti vit y si mil ar t o 
n o n d e pr e s s e d el d er s.  W e will al s o e x a mi n e w h et h er t h er e ar e diff er e n c e s i n t h e i nt er v al c h a n g e b et w e e n 
i n di vi d u al s w h o r e mit o n a cti v e dr u g a n d t h o s e w h o r e mit o n pl a c e b o. 
 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
D at a o n n e v er -d e pr e s s e d el d er s will b e dr a w n fr o m a s e p ar at e st u d y (I R B 1 3 0 3 6 0 , Fr o nt al H y p o p erf u si o n 
Eff e ct s o n A nti d e pr e s s a nt O ut c o m e s i n L at e -Lif e D e pr e s si o n, PI: T a yl or).  W e a nti ci p at e t h at r e s ult s fr o m t hi s 
s u b st u d y will i nf or m t h e  a p pli c ati o n f or t hi s pr oj e ct’ s c o m p etiti v e r e n e w al.  
 
1 2. 0 . P O T E N TI A L RI S K S   
1.  I nt er vi e w, e m er g e n ci e s, a n d p o s si bl e s ui ci d al i d e ati o n.  S u bj e ct s m a y e x p eri e n c e di s c o mf ort d uri n g t h e 
cli ni c al i nt er vi e w a n d e v al u ati o n s w h e n di s c u s si n g s y m pt o m s, lif e e v e nt s, a n d s o ci al s u p p ort.  T h e Pr oj e ct 
C o or di n at or will b e e x p eri e n c e d a n d s kill e d i n i nt er vi e wi n g d e pr e s s e d s u bj e ct s.  S h o ul d t h e s u bj e ct wi s h t o 
st o p or t a k e a br e a k, t h e c o or di n at or will all o w it.  A st u d y d o ct or will b e a v ail a bl e a s a b a c k u p.  I n a d diti o n, 
s h o ul d t h e s u bj e ct e x pr e s s s ui ci d al i d e ati o n at a n y ti m e d uri n g t h e i nt er vi e w, a st u d y d o ct or will b e 
c o nt a ct e d i m m e di at el y t o a s s e s s t h e s u bj e ct a n d t o d et er mi n e t h e a p pr o pri at e c o ur s e of a cti o n.  T h o u g ht s 
of s ui ci d e will b e t a k e n v er y s eri o u sl y.  O pti o n s f o r a d dr e s si n g t hi s m a y i n cl u d e c o nt a cti n g t h e i n di vi d u al’ s 
m e nt al h e alt h c ar e gi v er, r ef erri n g f or ur g e nt e v al u ati o n a n d tr e at m e nt, or e m er g e nt e v al u ati o n a n d 
h o s pit ali z ati o n.  Si mil ar pr a cti c e s will b e u s e d f or ot h er e m er g e n ci e s, i n cl u di n g b ut n ot li mit e d t o p s y c h o si s, 
h o mi ci d al or vi ol e nt t h o u g ht s, or a n a c ut e c h a n g e i n a s u bj e ct’ s p h y si c al st at u s.  
 
2.  U n bli n di n g: It i s p o s si bl e t h at it m a y b e cr u ci al t o d efi niti v el y i d e ntif y w h at st u d y dr u g a p arti ci p a nt i s 
r e c ei vi n g t o pr o vi d e o pti m al c ar e.  W e will o nl y br ea k t h e bli n d if k n o wl e d g e of t h e st u d y dr u g i n P h a s e 1 
( e s cit al o pr a m or pl a c e b o) i s n e c e s s ar y t o pr o vi d e o pti m al tr e at m e nt i n a n e m er g e n c y sit u ati o n.  If t h e 
e m er g e n c y sit u ati o n i s a n a d v er s e e v e nt, t hi s will b e r e c or d e d a n d r e p ort e d a s s u c h.  E m er g e n c y 
u n bli n di n g will b e c o n d u ct e d t hr o u g h t h e V a n d er bilt I n v e sti g ati o n al Dr u g S er vi c e, w h o i s pr o vi di n g st u d y 
dr u g a n d bli n di n g pr o c e d ur e s.  T h e y h a v e 2 4 -h o ur a c c e s s f or e m er g e n c y u n bli n di n g.  
 
3.  A nti d e pr e s s a nt Si d e Eff e ct s:  W e will f or m all y a s s e s s si d e eff e ct s at e a c h pl a n n e d c o nt a ct a n d i nf or m all y a s 
n e e d e d t hr o u g h a d diti o n al or u n s c h e d ul e d c all s.  W e will att e m pt t o mi ni mi z e si d e eff e ct s b y sl o w titr ati o n 
a n d all o w a n c e f or d o s e r e d u cti o n if n e e d e d.  W e will wit h dr a w s u bj e c t s fr o m t h e st u d y if t h e y c a n n ot 
t ol er at e t h e l o w e st d o s e of 1 0 m g of e s cit al o pr a m  or pl a c e b o e q ui v al e nt d uri n g p h a s e 1 or 1 5 0 m g of 
b u pr o pi o n xl d uri n g p h a s e 2.  
W e d e s cri b e b el o w s o m e of t h e m or e c o m m o n or p arti c ul arl y c o n c er ni n g si d e eff e ct s.  T h er e i s al w a y s 
t h e p ot e nti al f or t h e d e v el o p m e nt of r ar e, u n a nti ci p at e d si d e eff e ct s.  I n g e n er al, w e will c ar ef ull y a s s e s s 
s u bj e ct s wit h n e w c o m pl ai nt s t o d et er mi n e if t h e y m a y b e r el at e d t o st u d y dr u g a n d if t h er e i s a n e e d f or 
cl o s er m o nit ori n g or c h a n g e i n st u d y dr u g d o si n g.  
a.  E s cit al o pr a m c o m m o n si d e eff e ct s : Alt h o u g h g e n er all y w ell t ol er at e d, e s cit al o pr a m d o e s c arr y ri s k 
of si d e eff e ct s.  T h e s e i n cl u d e: d er m at ol o gi c al (r a s h), g a str oi nt e sti n al ( dr y m o ut h, n a u s e a, di arr h e a, 
c o n sti p ati o n), n e ur ol o gi c al ( di z zi n e s s,  vi vi d dr e a m s), s y st e mi c (f ati g u e, s o m n ol e n c e or i n s o m ni a, 
a p p etit e c h a n g e, w ei g ht l o s s/ g ai n, s w e ati n g), a n d s e x u al d y sf u n cti o n.  
b.  B u pr o pi o n c o m m o n si d e eff e ct s : Li k e wi s e, b u pr o pi o n i s g e n er all y w ell t ol er at e d.  C o m m o n si d e 
eff e ct s i n cl u d e: d er m at ol o gi c al (r a s h), g a str oi nt e sti n al ( n a u s e a, di arr h e a, c o n sti p ati o n, dr y m o ut h), 
n e ur ol o gi c al ( di z zi n e s s, h e a d a c h e, ti n nit u s, tr e m or, vi vi d dr e a m s), p s y c hi atri c ( a n xi et y, a git ati o n), or 
s y st e mi c (i n s o m ni a, a p p etit e a n d/ or w ei g ht l o s s, s w e ati n g).  T h er e ar e al s o r ar e ri s k s of s ei z ur e s or 
St e v e n s -J o h n s o n s y n dr o m e, w hi c h w e a d dr e s s t hr o u g h o ur e ntr y crit eri a.  
 
c.  S ui ci d e ri s k : A nti d e pr e s s a nt-i n d u c e d s ui ci d alit y i s a n i m p ort a nt c o n c er n a n d o n e t h at h a s r e s ult e d i n 
a bl a c k -b o x w ar ni n g o n a nti d e pr e s s a nt s b y t h e F D A.  W e will b ot h i nf or m s u bj e ct s of t hi s p ot e nti al 
ri s k a n d m o nit or f or s ui ci d alit y at e a c h c o nt a ct.  S h o ul d a n y p o s si bl e s ui ci d alit y b e d et e ct e d, a st u d y 
d o ct or will a s s e s s t h at i n di vi d u al a n d a ct a c c or di n gl y ( s e e It e m 1 a b o v e).  
d.  Di s c o nti n u ati o n S y n dr o m e : Di s c o nti n u ati o n s y n dr o m e, s e e n wit h a br u pt c e s s ati o n of a nti d e pr e s s a nt 
dr u g s, m a y c a u s e a v ari et y of n e ur ol o gi c al ( di z zi n e s s, v erti g o, i n s o m ni a, tr e m or, p ar e st h e si a s), 
g a str oi nt e sti n al ( n a u s e a, a b d o mi n al cr a m pi n g), s y st e mi c (l et h ar g y, fl u -li k e s y m pt o m s) a n d 
p s y c hi atri c s y m pt o m s (irrit a bilit y, a n xi et y, d y s p h ori a).  W e will pr o vi d e a m e di c ati o n t a p er f or 
i n di vi d u al s w h o wi s h t o st o p e s cit al o pr a m at t h e st u d y’ s e n d. 
 
4.  Ri s k of Pl a c e b o:   T h e pri m ar y c o n c er n wit h u s e of pl a c e b o i s t h at i n di vi d u al s r e c ei vi n g pl a c e b o will f ail t o 
i m pr o v e or w or s e n o v er t h e c o ur s e of t h e pl a c e b o p eri o d.  W e mi ni mi z e t hi s ri s k b y u si n g a s h ort er st u d y ( 8 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
w e e k s i n c o ntr a st t o 1 0 or 1 2 w e e k s) a n d u s e of wit h dr a w al crit eri a, i n cl u di n g w or s e ni n g d e pr e s si o n 
(“ st o p pi n g r ul e s” –  s e e S e cti o n 1 2 b el o w).  W e f urt h er mi ni mi z e t hi s ri s k b y a n u n e q u al all o c ati o n of 
s u bj e ct s i n p h a s e 1 t o e s cit al o pr a m or pl a c e b o i n a 2: 1 r ati o.  S u c h a n a p pr o a c h i s f e a si bl e a s w e ar e n ot 
t e sti n g f or dr u g effi c a c y b ut e x a mi ni n g n e ur al pr e di ct or s of r e mi s si o n, w hi c h w e h y p ot h e si z e w oul d diff er 
b et w e e n e s cit al o pr a m a n d pl a c e b o.  
 
5.  A nti d e pr e s s a nt M e di c ati o n s: E n d of St u d y Pr o c e d ur e s:  D uri n g t h e c o ur s e of t h e st u d y w e will w or k wit h 
st u d y s u bj e ct s t o i d e ntif y pr o vi d er s w h o will c o nti n u e t h eir c ar e at t h e e n d of t h e st u d y.  F or t h o s e s u bj e c t s 
w h o wi s h t o c o nti n u e o n t h eir e n d -of -st u d y dr u g, w e will pr o vi d e pr e s cri pti o n s, t w o fr e e vi sit s, a n d a s si st 
wit h arr a n gi n g f oll o w -u p cli ni c vi sit s wit h t h eir pr o vi d er.  If t h e y d o n ot wi s h t o c o nti n u e o n st u d y dr u g, w e 
will al s o r ef er t o cli ni c al pr o vi d er s, b ut al s o w or k t o sl o wl y di s c o nti n u e t h e st u d y dr u g t o a v oi d 
di s c o nti n u ati o n eff e ct s.  
 
6.  M a g n eti c R e s o n a n c e I m a gi n g.   Alt h o u g h t hi s pr o c e d ur e i s g e n er all y l o w -ri s k, t h er e ar e p arti c ul ar c o n c er n s.  
I n di vi d u al s will b e s cr e e n e d f or t h e pr e s e n c e of i m pl a nt ed m et al (i n cl u di n g b ut n ot li mit e d t o m e di c al 
d e vi c e s, s hr a p n el, t att o o s or p er m a n e nt m a k e u p); t h o s e w h o s cr e e n p o siti v e will b e e x cl u d e d fr o m t h e 
st u d y.  Cl a u str o p h o bi a i s al s o a n i s s u e f or m a n y p ot e nti al s u bj e ct s.  D uri n g t h e M RI, s u bj e ct s will h a v e 
v oi c e c o nt a ct wit h a r a di ol o g y t e c h ni ci a n, a n d m a y r e q u e st t h e s c a n b e st o p p e d at a n y ti m e.  
 
7.  I n ci d e nt al Fi n di n g s: M a g n eti c R e s o n a n c e I m a gi n g: A n ot h er ri s k i s t h e o c c urr e n c e of i n ci d e nt al fi n di n g s o n 
M RI.  All s c a n s ar e r e vi e w e d at ti m e of a c q ui siti o n a n d c o n c e r ni n g fi n di n g s ar e di s c u s s e d wit h a n att e n di n g 
n e ur or a di ol o gi st .  S h o ul d a n y c o n c er ni n g fi n di n g s b e s e e n, a st u d y d o ct or will c o n v e y t h e s e fi n di n g s t o t h e 
s u bj e ct al o n g wit h  r e c o m m e n d ati o n s f or f urt h er e v al u ati o n, a n d f a cilit at e r ef err al s f or s u c h  e v al u ati o n a n d 
tr e at m e nt. 
 
8.  Br e a c h of c o nfi d e nti alit y:   T h er e i s t h e p ot e nti al ri s k of br e a c h of c o nfi d e nti alit y of cli ni c al, g e n eti c, a n d 
l a b or at or y i nf or m ati o n.  T h e PI, Dr. T a yl or, h a s e xt e n si v e e x p eri e n c e a s a cli ni c al i n v e sti g at or d e ali n g wit h 
s u c h s e n siti v e i nf or m ati o n, a n d a s a pr e vi o u s m e m b er of a n I n stit uti o n al R e vi e w B o ar d h a s e x p eri e n c e 
a s s uri n g t h at d at a i s a d e q u at el y pr ot e ct e d.  S af e g u ar d s t o pr ot e ct c o nfi d e nti alit y i n cl u d e l o c k e d r e c or d s 
a n d fir e w all s ar o u n d p a s s w or d -pr ot e ct e d el e ctr o ni c d at a, a n d all st u d y d at a b ei n g c o d e d, wit h t h e k e y 
li n ki n g t h e c o d e wit h a s u bj e ct’ s i d e ntit y b ei n g k e pt i n a s e p ar at e, l o c k e d fil e. 
 
1 3. 0 . A D V E R S E E V E N T R E P O R TI N G: 
W e d efi n e a n a d v er s e e v e nt a s a n y a d v er s e c h a n g e i n h e alt h or d e v el o p m e nt of a si d e eff e ct o c c urri n g i n a 
st u d y p arti ci p a nt aft er e nr oll m e nt.  T h e s e m a y b e e x p e ct e d e v e nt s ( k n o w n dr u g eff e ct s, a s d et ail e d i n t h e 
c o n s e nt f or m, s af et y m o nit ori n g pl a n, or p a c k a g e i n s ert) or u n e x p e ct e d e v e nt s.  W e d efi n e a s eri o u s a d v er s e 
e v e nt a s a n y e v e nt t h at r e s ult s i n h o s pit ali z ati o n, di s a bilit y or p er m a n e nt d a m a g e, i s lif e t hr e at e ni n g, r e s ult s i n 
d e at h, or a n y ot h er s eri o u s e v e nt t h at d o e s n ot fit t h e s e o ut c o m e s, b ut r e q uir e ur g e nt m e di c al i nt er v e nti o n.  
 
W e will c ar ef ull y m o nit or a d v er s e e v e nt s t hr o u g h o ut t h e s t u d y.  S u bj e ct s will b e a s s e s s e d f or s af et y, 
m e di c ati o n t ol er a bilit y, a n d u n a nti ci p at e d pr o bl e m s at e a c h c o nt a ct.  E m er g e n c y c o nt a ct i nf or m ati o n will b e  
 
pr o vi d e d t o e a c h s u bj e ct f or ur g e nt, u n a nti ci p at e d pr o bl e m s.  All a d v er s e e v e nt s will b e r e vi e w e d b y Dr. T a yl or 
at l e a st w e e kl y. All A E s, r e g ar dl e s s of b ei n g j u d g e d a s r el at e d or n o n -r el at e d, will b e s u m m ari z e d a n d i n cl u d e d 
i n t h e a n n u al I R B c o nti n ui n g r e vi e w. A ll S A E s will b e r e p ort e d t o t h e V a n d er bilt I R B a n d V A T V H S I R B  wit hi n 7  
w or ki n g d a y s.  Dr. T a yl or will h a v e r e s p o n si bilit y  f or t hi s r e p orti n g r e q uir e m e nt.  A d diti o n all y, w or ki n g i n 
c oll a b or ati o n wit h t h e I R B, h e will a s s ur e t h at r e p ort a bl e a d v er s e e v e nt s ar e al s o r e p ort e d t o NI H.  
 
A s t hi s st u d y will u s e F D A a p pr o v e d a nti d e pr e s s a nt m e di c ati o n s, i s n ot a m ulti -sit e cli ni c al tri al, a n d i s n ot a 
P h a s e III cli ni c al tri al, w e will n ot e st a bli s h a f or m al D S M B f or t hi s st u d y.  A s P h a s e 1 i s pl a c e b o -c o ntr oll e d a n d 
bli n d e d, w e di d c o n si d er i niti ati o n of a D S M B b ut i n c o nj u n cti o n wit h NI H pr o gr a m offi c er s ulti m at el y d e ci d e d it 
w a s n ot n e c e s s ar y d u e t o t h e l o n g hi st or y of e x p eri e n c e wit h e s cit al o pr a m, it s o v er all t ol er a bilit y, a n d e x c ell e nt 
s af et y pr ofil e. P er NI H r e q u e st, pri or t o i niti at i n g e nr oll m e nt w e h a v e n a m e d Dr. R o n al d C o w a n a s t h e  
i n d e p e n d e nt s af et y m o nit or.  H e  will r e vi e w all s af et y e v e nt s i n a bli n d e d f or m at e v er y 6 m o nt h s w hil e s u bj e ct s 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
ar e p arti ci p ati n g i n t h e st u d y.  If, aft er r e vi e wi n g t h e bli n d e d d at a , h e i s c o n c er n e d a b o ut a d v er s e e v e nt r at e s, 
h e m a y r e q u e st u n bli n d e d d at a.  I n a d diti o n t o ot h er r e p orti n g r e q uir e m e nt s, h e  will al s o r e vi e w a n y s eri o u s 
a d v er s e e v e nt s ( S A E s) wit hi n 7 d a y s.  Dr. C o w a n’ s c o n cl u si o n s aft er e a c h d at a r e vi e w will b e pr o vi d e d t o t h e 
V a n d er bilt I R B a n d V A T V H S I R B wit h e a c h c o nti n ui n g r e vi e w.  
 
1 4. 0 . S T U D Y WI T H D R A W / DI S C O N TI N U A TI O N  
P arti ci p a nt s m a y wit h dr a w fr o m t h e st u d y at a n y ti m e.  If p arti ci p a nt s l e a v e t h e st u d y e arl y, w e will r e c o m m e n d 
a m e di c ati o n t a p er a n d cli ni c al r ef err al s f or f urt h er c ar e.   
 
A p arti ci p a nt will b e wit h dr a w n fr o m t h e st u d y if: 
1)  T h e p arti ci p a nt  wit h dr a w s hi s or h er c o n s e nt  
2)  T h e PI c o n si d er s it i s i n t h e b e st i nt er e st of t h e p ati e nt f or hi m or h er t o st o p st u d y p arti ci p ati o n  
3)  I n t h e PI’ s j u d g m e nt, t h e p arti ci p a nt’ s d e pr e s si v e s y m pt o m s h a v e w or s e n e d si g nifi c a ntl y si n c e st u d y dr u g 
i niti ati o n 
4)  T h e p ati e nt d e v el o p s s ui ci d al i d e ati o n w h er e h e or s h e s h o ul d b e r ef err e d f or r e g ul ar cli ni c al c ar e f or s af et y  
5)  T h e p ati e nt i s l o st t o f oll o w -u p  
 
If a p arti ci p a nt d e v el o p s w or s e ni n g d e pr e s si o n ( b ut n ot s ui ci d alit y) or i nt ol er a bl e a d v er s e e v ent s d uri n g bli n d e d 
P h a s e 1, t h e s u bj e ct d o e s n ot h a v e t o b e wit h dr a w n b ut c a n i n st e a d pr o c e e d t o o p e n -l a b el P h a s e 2.  
Ot h er wi s e, p arti ci p a nt s will b e r ef err e d f or cli ni c al tr e at m e nt.  W e will off er t w o fr e e vi sit s w h e n t h e y fi ni s h t h e 
st u d y a n d will di s c u s s f urt h er tr e at m e nt o pti o n s.  
 
1 5. 0 S T A TI S TI C A L C O N SI D E R A TI O N S   
F or Ai m 1 , i nt er-c orr el ati o n m atri c e s a n d s c att er pl ot s will b e u s e d t o a s s e s s a n d vi s u ali z e t h e p att er n s of 
a s s o ci ati o n a m o n g t h e tr a ct W M L v al u e s a n d r e s p e cti v e f M RI c o n n e cti vit y v al u e s. M ulti v ari at e a n al y si s will b e 
c o n d u ct e d u si n g c a n o ni c al c orr el ati o n. C a n o ni c a l c orr el ati o n c a n a c c o m m o d at e m or e t h a n o n e v ari a bl e o n 
b ot h t h e i n d e p e n d e nt a n d d e p e n d e nt si d e s of t h e g e n er al li n e ar m o d eli n g e q u ati o n a n d t h o s e v ari a bl e s m a y b e 
eit h er m etri c or n o n m etri c. I n c a n o ni c al a n al y si s, t h e s ol uti o n d e p e n d s b ot h o n c orr el ati o n s  a m o n g t h e 
v ari a bl e s i n e a c h s et a n d o n c orr el ati o n s a m o n g v ari a bl e s b et w e e n s et s. I n a si m ult a n e o u s pr o c e s s, u n d erl yi n g 
c a n o ni c al v ari at e s ( or f a ct or l o a di n g s) c o m pri si n g t h e W M L v al u e s  o n t h e i n d e p e n d e nt si d e will b e c o n str u ct e d 
i n s u c h a w a y t o m a xi mi z e t h e c orr el ati o n s wit h c a n o ni c al v ari at e s of t h e f M RI v al u e s o n t h e d e p e n d e nt si d e. 
T h e s a m e a s s u m pti o n s a s t h o s e u n d erl yi n g m u lti pl e li n e ar r e gr e s si o n a p pl y.  Ev al u ati o n s of n or m alit y, li n e arit y, 
a n d h o m o s c e d a sti cit y will b e c o n d u ct e d, a s will t e st s of m u lti c olli n e arit y a n d si n g ul arit y of t h e u n d erl yi n g 
c orr el ati o n m atri c e s. Si m pl e bi v ari at e c orr el ati o n s a n d s c att er pl ot s will a s si st wit h d e s cri bi n g a n d vi s u all y t h e 
p att er n s of a s s o ci ati o n, c a n o ni c al c orr el ati o n will c o ntr ol f or t h e i nt er -c orr el ati o n s a m o n g  t h e W M L a n d f M RI 
v al u e s will m a xi mi zi n g t h e c orr el ati o n b et w e e n t h e t w o s et s.  C o v ari at e s of a g e, s e x, a n d v a s c ul ar ri s k  will b e 
i n cl u d e d wit h t h e W M L m e a s ur e s. Eff e ct s of M A D R S a n d t ot al  br ai n W M L  v ol u m e  will al s o b e e x a mi n e d.   W e 
will u s e a si mil ar a p pr o a c h t o e x a mi n e h o w W M L v al u e s ar e a s s o ci at e d wit h cli ni c al pr e s e nt ati o n .  F or 
H y p ot h e si s 1, att e nti o n, m e m or y, a n d pr o c e s si n g s p e e d s c or e s will b e o n t h e d e p e n d e nt si d e.  F or H y p. 2, 
B RI S C a n d b a s eli n e M A D R S s c or e s will b e o n t h e d e p e n d e nt si d e.  
F or t h e f MRI e m oti o n al d ot -pr o b e  t a s k, w e will e x a mi n e h o w W M L s ar e a s s o ci at e d wit h R OI 
a cti v ati o n( E x pl or at or y H y p).  S p e cifi c all y, w e will e x a mi n e h o w C B m e a s ur e s ar e a s s o ci at e d wit h a cti vit y i n 
D M N a n d C C N r e gi o n s d uri n g t h e t a s k’ s att e nti o n al c o m p o n e nt a n d h o w U F  m e a s ur e s ar e a s s o ci at e d wit h 
a m y g d al a a cti vit y d uri n g t h e aff e cti v e c o m p o n e nt. I n t hi s a n al y si s W M L m e a s ur e s will b e o n t h e "i n d e p e n d e nt" 
si d e of t h e c a n o ni c al c orr el ati o n w hil e f M RI a cti v ati o n v al u e s will b e " d e p e n d e nt" si d e.  
W e will u s e a si mil ar a p pr o a c h f or E x pl or at or y Ai m 1 , w h er e w e e x a mi n e h o w c o g niti v e t e st p erf or m a n c e 
m a y s er v e a s a m ar k er of W M L tr a ct d a m a g e.  I n cl u di n g t h e pr e vi o u s c o v ari at e s pl u s e d u c ati o n, c o g niti v e t e st 
r e s ult s will b e o n t h e i n d e p e n d e nt si d e wit h tr a ct W M L v al u e s o n t h e d e p e n d e nt si d e. 
D at a fr o m n o n d e pr e s s e d el d er s will b e i nt e gr at e d i nt o t h e a b o v e a n al y s e s.  W e will t e st f or gr o u p 
diff er e n c e s i n t h e n e ur oi m a gi n g a n d c o g niti v e m e a s ur e s d e s cri b e d a b o v e.  W e will al s o i n cl u d e a gr o u p 
v ari a bl e ( d e pr e s s e d or n ot d e pr e s s e d) i n a n al y s e s.  
Ai m 2  e x a mi n e s h o w tr a ct m e a s ur e s pr e di ct r e mi s si o n. F oll o wi n g o ur pr e vi o u s a p pr o a c h (2 1 ), o ur 
d efi niti o n of r e mi s si o n i s M A D R S ≤ 7.  S e c o n d aril y, w e will e x a mi n e dr u g r e s p o n s e ( 5 0 % i m pr o v e m e nt o n 
M A D R S). R e mi s si o n / r e s p o n s e st at u s f or s u bj e ct s wit h mi s si n g d at a will b e e sti m at e d vi a m ulti pl e i m p ut ati o n 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
m et h o d a s s u mi n g t h at dr o p o ut s ar e mi s si n g at r a n d o m.  
W e will u s e t w o r e gr e s si o n m o d el s t o t e st f or m e di ati o n w hil e a dj u sti n g f or b a s eli n e M A D R S, a g e, s e x, a n d 
v a s c ul ar ri s k. T o a s s e s s i n dir e ct eff e ct s of tr a ct W M L a n d F C m ea s ur e s a s  m e di at or v ari a bl e s , w e will r e gr e s s 
a p ot e nti al m e di at or o n a tr a ct -b a s e d m e a s ur e ( a n e x pl a n at or y v ari a bl e of i nt er e st). W e will fit a n ot h er m o d el i n 
w hi c h a nti d e pr e s s a nt r e mi s si o n or n o nr e mi s si o n s er v e s  a s o ut c o m e v ari a bl e , a n d  t h e p ot e nti al m e di at or a n d 
tr a ct-d eri v e d m e a s ur e  s er v e a s c o v ari at e s. T h e s e c o n d m o d el c a n b e eit h er l o gi sti c or li n e ar r e gr e s si o n m o d el 
d e p e n di n g o n t h e n at ur e of o ut c o m e. T h e pr o d u ct of t w o b et a  c o effi ci e nt s c orr e s p o n di n g t o t h e tr a ct -b a s e d 
m e a s ur e i n t h e fir st m o d el a n d t o t h e m e di ati o n v ari a bl e i n t h e s e c o n d m o d el will b e a s s e s s e d b y c o n str u cti n g 
b o ot str a p p e d 9 5 % c o nfi d e n c e i nt er v al s ( CI); st ati sti c all y si g nifi c a nt diff er e n c e fr o m z er o i m pli e s t h at t h e 
r elati o n s hi p b et w e e n t h e o ut c o m e  a n d e x pl a n at or y v ari a bl e i s m e di at e d  b y t h e v ari a bl e i n q u e sti o n (1 2 7 ,1 2 8 ). 
T hi s a p pr o a c h will sli g htl y diff er f or e a c h st u d y p h a s e. F or P h a s e 1, m o d el s will i n cl u d e dr u g ar m ( pl a c e b o 
or e s cit al o pr a m).  T o e x a mi n e f or diff er e n c e s i n h o w tr a ct i m p air m e nt aff e ct s r e mi s si o n i n e a c h ar m, w e will 
t e st f or i nt er a cti o n s b et w e e n dr u g a s si g n m e nt a n d tr a ct i nt e grit y ( W M L & F C).  W e will e x pl or e si g nific a nt 
i nt er a cti o n s i n i n di vi d u al m o d el s.  F or s u bj e ct s e nt eri n g P h a s e 2, w e will t e st f or diff er e n c e s i n tr a ct i nt e grit y 
( W M L & F C) b et w e e n t h o s e ori gi n all y a s si g n e d t o e s cit al o pr a m a n d pl a c e b o.  If diff er e n c e s ar e o b s er v e d, i n 
m o d el s w e will c o ntr ol f or or i gi n al P h a s e 1 c o h ort a s si g n m e nt. I n e x pl or at or y m o d el s , w e will u s e si mil ar 
a p pr o a c h e s t o t e st  f or t h e a d diti o n al eff e ct of c o g niti v e d o m ai n f u n cti o n ( T a bl e 5 ) o n r e mi s si o n .  W e will al s o 
u s e t hi s a p pr o a c h f or E x pl or at or y Ai m 2  w h e n w e e x a mi n e t h e eff e ct of c o n n e cti vit y d efi cit s i n ot h er tr a ct s.  
I m p ort a ntl y, t h e r el ati o n s hi p b et w e e n c o n n e cti vit y a n d a nti d e pr e s s a nt r e s p o n s e m a y n ot b e li n e ar.  It i s 
p o s si bl e t h at a ‘t hr e s h ol d’ m u st b e cr o s s e d i n or d er f or tr a ct c o n n e cti vit y d efi cit s t o i nfl u e n c e r e s p o n s e  (3 ).  T o 
pr o p erl y t a k e i nt o a c c o u nt n o nli n e ar eff e ct of a c o nti n u o u s pr e di ct or v ari a bl e ( e. g., W M L, F C ) o n r e s p o n s e 
v ari a bl e ( e. g., r e mi s si o n or n o nr e mi s si o n) i n t h e m o d el s , w e will e m pl o y r e stri ct e d c u bi c s pli n e s of t h e 
pr e di ct or. St ati sti c al si g nifi c a n c e of t h e n o nli n e ar t er m s vi a F -t e st i m pli e s t h at t h e r el ati o n s hi p b et w e e n t h e t w o 
m e a s ur e s of i nt er e st c a n b e n o nli n e ar.  
 
 
1 5. 1 . S a m pl e Si z e a n d St ati sti c al P o w er : 
Ai m 1 : Fr o m o ur p u bli s h e d r e p ort (1 2 9 ) c orr el ati o n s of t h e 
F C of t h e P F C wit h t h e a m y g d al a a n d t h e hi p p o c a m p u s w er e 
i n t h e r a n g e of 0. 5 2 t o 0. 5 5. A s a m pl e of 1 3 0 s u bj e ct s, will 
h a v e > 9 0 % st ati sti c al p o w er f or a s s o ci ati o n s > = 0. 3 0 (t w o -
t ail e d al p h a = 0. 0 5).  H o w e v er, o ur pri m ar y a p pr o a c h t o t h e 
a n al y si s of Ai m 1 will u s e c a n o ni c al c orr el a ti o n wit h n o k n o w n 
p o w eri n g al g orit h m s; s a m pl e si z e a n d eff e ct e sti m at e s ar e 
u s e d t o g ui d e t h e a p pr o pri at e n e s s. U si n g t h e m ulti pl e 
r e gr e s si o n a p pr o a c h ( si n gl e d e p e n d e nt) a s a c o n s er v ati v e 
e sti m at e, a s a m pl e si z e of 1 3 0 a c hi e v e s 8 3 % st ati sti c al p o w er t o d et e ct a n R 2  a s s m all a s 0. 0 6 ( st a n d ar di z e d 
b et a = 0. 2 0, 6 % s h ar e d v ari a n c e) attri b ut e d t o t h e a s s o ci ati o n of W M L wit h a si g ni fi c a n c e l e v el ( al p h a) of 0. 0 5 
aft er a dj u sti n g f or ot h er pr o p o s e d c o v ari at e s. T h e s e c al c ul ati o n s a s s u m e t h at t h e v ari a bl e s f or w hi c h w e ar e 
a dj u sti n g h a v e a n R 2  of  0. 1 0 ( 1 0 %) (1 3 0 ). W e s u s p e ct t h at t h e c o ntr ol v ari a bl e s will h a v e a hi g h er i nt er -
c orr el ati o n v al u e, t h u s i n cr e a si n g o ur p o w er f or t e sti n g t h e eff e ct of a si n gl e v ari a bl e.   
 
Ai m 2 : T h e st u d y i n cl u d e s a pl a c e b o ar m t o i d e ntif y eff e ct s s p e cifi c t o a n a cti v e d e pr e s s a nt w hil e h a vi n g a 
c o m p ar a bl e n u m b er of s u bj e ct s r e c ei vi n g e a c h a cti v e dr u g.  P o w eri n g t h e st u d y f or P h a s e 1, T a bl e 2  pr e s e nt s 
e sti m at e s f or o ur pr o p o s e d s a m pl e si z e u si n g u n a dj u st e d eff e ct s of l o w v s. hi g h W M L v al u e s o n t h e r e s p e cti v e  
 
o ut c o m e s of i nt er e st f o u n d i n o ur pr eli mi n ar y d at a. T h e l o gi sti c r e gr e s si o n a p pr o a c h all o w s f or t h e t e sti n g of 
eff e ct s a dj u s t e d f or k n o w n c o v ari at e s. U si n g t hi s a p pr o a c h, a ss u mi n g a b a s e n o n -r e mitt a n c e r at e of 0. 3 6 
( 3 6 %), a s a m pl e si z e of 1 3 0 will e n a bl e u s t o d et e ct a l o g h a z ar d r ati o a s s m all a s 0. 4 5 f or a s p e cifi c m e a s ur e. 
W e c o n s er v ati v el y i n cl u d e d a n a s s u m pti o n t h at c o v ari at e s w o ul d a c c o u nt t o u p t o 1 0 % s h ar e of t h e eff e ct o n 
n o n r e mi s si o n. If t h at v al u e i s l e s s, o ur st ati sti c al p o w er will i n cr e a s e f or t h e s a m e h a z ar d r ati o. U si n g hi g h v s. 
l o w tr a ct W M L v ol u m e a s a n e x a m pl e, aft er c o ntr olli n g f or ot h er eff e ct s, o ur s a m pl e will e n a bl e u s t o d et e ct a n 
eff e ct o n t h e li k eli h o o d of n o n -r e mitt a n c e of at l e a st 2 5 % ( hi g h W M L v s. l o w W M L, 0. 4 5 / 0. 3 6 = 1. 2 5 or 2 5 % 
i n cr e a s e). C o nti n u o u s a s w ell a s n o nli n e ar  o p er ati o n ali z ati o n of eff e ct s will b e e x a mi n e d .  
 
1 6. 0  P RI V A C Y A N D C O N FI D E N TI A LI T Y  
T a bl e 2 . Ai m 2 P o w er E sti m at e s 
R e gi o n  
L o w W M L  
Hi g h W M L  
P o w er  
(α  = 0. 0 5)  
B a s eli n e M A D R S  
•  U F, R  
2 1. 0 ( 1 2. 2)  
2 9. 5 ( 3. 0)  
0. 9 8  
•  A T R, R  
1 7. 4 ( 8. 6)  
2 9. 7 ( 9. 0)  
1. 0 0  
3 -M o nt h M A D R S  
•  A nt. C B, L  
8. 8 ( 7. 0)  
1 4. 8 ( 5. 8)  
0. 9 9  
•  P o st. C B, R  
7. 7 ( 7. 6)  
1 4. 6 ( 7. 8)  
0. 9 9  
•  P o st. C B, L  
5. 2 ( 2. 9)  
1 6. 0 ( 7. 6)  
1. 0 0  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
C o nfi d e nti alit y Pr o c e d ur e s : A s t h e PI, Dr. T ayl or will a s s ur e all pr o c e d ur e s pr ot e cti n g st u d y d at a d e si g n e d t o 
g u ar d s u bj e ct c o nfi d e nti alit y c o nf or m t o t h e V a n d er bilt  H u m a n R e s e ar c h Pr ot e cti o n Pr o gr a m r e q uir e m e nt s.  
A d diti o n all y, t h e V a n d er bilt  I R B m u st a p pr o v e all pr o c e d ur e s a n d s af et y pr e c a uti o n s b ef or e t h e st u d y c a n 
b e gi n.  All n o n -el e ctr o ni c d at a ( cli ni c al e v al u ati o n s , p a p er a s s e s s m e nt s) will b e st or e d s e c ur el y i n l o c k e d 
offi c e s or l a b or at ori e s a c c e s si bl e o nl y b y st u d y st aff.  All el e ctr o ni c d at a will b e st or e d i n s e c ur e d s er v er s wit h 
li mit e d a c c e s s.  R e d C A P will b e u s e d f or d at a m a n a g e m e nt. 
 
F urt h er, all i nf or m ati o n t h at c o ul d p ot e nti all y dir e ctl y i d e ntif y a s u bj e c t i s r e m o v e d fr o m all st u d y d at a.  T hi s 
i n cl u d e s M RI d at a,  el e ctr o ni c a n d p a p er a s s e s s m e nt s.  Dir e ct i d e ntifi er s  will b e r e pl a c e d wit h a u ni q u e f o ur -
di git c o d e.  T h e k e y t o li n ki n g t h e c o d e t o s u bj e ct i d e ntit y will b e k e pt s e p ar at el y fr o m st u d y d at a, i n a l o c k e d 
fil e i n p a s s w or d-pr ot e ct e d c o m p ut er i n Dr. T a yl or’ s offi c e. O nl y st u d y st aff i n v ol v e d i n cli ni c al r e cr uit m e nt a n d 
a s s e s s m e nt will h a v e a c c e s s t o i n di vi d u all y i d e ntifi a bl e pri v at e i nf or m ati o n.  All ot h er st u d y st aff , i n cl u di n g 
i m a g e a n al y st s, will b e bli n d e d t o s u bj e ct i d e ntit y a n d  will o nl y h a v e a c c e s s t o t h e c o d e d i d e ntifi er.  
 
Pri v a c y Pr o c e d ur e s : I nf or m e d c o n s e nt a n d all st u d y pr o c e d ur e s  will o c c ur i n pri v at e r e s e ar c h offi c e s a n d 
pri v at e r e s e ar c h e x a mi n ati o n r o o m s.  
 
1 7 . 0 F O L L O W-U P A N D R E C O R D S R E T E N TI O N :  
St u d y r e c or d s will b e m ai nt ai n e d f or at l e a st si x y e ar s aft er t h e st u d y i s cl o s e d wit h t h e I R B.  Aft er t h at ti m e, 
st u d y d at a m a y b e d e str o y e d or a n o n y mi z e d, m e a ni n g all li n k s t o dir e ct i d e ntifi er s will b e d e str o y e d.  A n y st u d y 
d at a i n t h e m e di c al r e c or d will b e k e pt i n d efi nit el y.  
 


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
LI T E R A T U R E CI T E D  
 
1.  
Al e x o p o ul o s G S, M e y er s B S, Y o u n g R C, C a m p b ell S, Sil b er s w ei g D, C h arl s o n M. ' V a s c ul ar 
d e pr e s si o n' h y p ot h e si s. Ar c h G e n P s y c hi atr y. 1 9 9 7; 5 4( 1 0): 9 1 5 -2 2.  
2.  
Kri s h n a n K R R, H a y s J C, B l a z er D G. M RI-d efi n e d v a s c ul ar d e pr e s si o n. A m J P s y c hi atr y. 
1 9 9 7; 1 5 4( 4): 4 9 7 -5 0 1.  
3.  
T a yl or W D, Ai z e n st ei n H J, Al e x o p o ul o s G S. T h e v a s c ul ar d e pr e s si o n h y p ot h e si s: M e c h a ni s m s 
li n ki n g v a s c ul ar di s e a s e wit h d e pr e s si o n. M ol P s y c hi atr y. 2 0 1 3; 1 8: 9 6 3-7 4. P M CI D: P M C 3 6 7 4 2 2 4.  
4.  
T a yl or W D, Z h a o Z, A s hl e y -K o c h A, P a y n e M E, St eff e n s D C, Kri s h n a n R R, et al. Fi b er tr a ct -
s p e cifi c w hit e m att er l e si o n s e v erit y Fi n di n g s i n l at e -lif e d e pr e s si o n a n d b y A G T R 1 A 1 1 6 6 C g e n ot y p e. 
H u m Br ai n M a p p. 2 0 1 3; 3 4( 2): 2 9 5 -3 0 3. P M CI D: P M C 3 7 7 2 5 2 2 . 
5.  
S h eli n e YI, Pri c e J L, V ai s h n a vi S N, Mi nt u n M A, B ar c h D M, E p st ei n A A, et al. R e gi o n al w hit e 
m att er h y p eri nt e n sit y b ur d e n i n a ut o m at e d s e g m e nt ati o n di sti n g ui s h e s l at e -lif e d e pr e s s e d s u bj e ct s 
fr o m c o m p ari s o n s u bj e ct s m at c h e d f or v a s c ul ar ri s k f a ct or s. A m J P s y c hi atr y. 2 0 0 8; 1 6 5( 4): 5 2 4-3 2.  
6.  
D al b y R B, C h a kr a v art y M M, A h di d a n J, S or e n s e n L, Fr a n d s e n J, J o n s d ottir K Y, et al. 
L o c ali z ati o n of w hit e -m att er l e si o n s a n d eff e ct of v a s c ul ar ri s k f a ct or s i n l at e -o n s et m aj or d e pr e s si o n. 
P s y c h ol M e d. 2 0 1 0; 4 0( 8): 1 3 8 9 -9 9.  
7.  
T a yl or W D, M a c F all J R, G eri g G, Kri s h n a n K R. Str u ct ur al i nt e grit y of t h e u n ci n at e f a s ci c ul u s i n 
g eri atri c d e pr e s si o n: R el ati o n s hi p wit h a g e of o n s et. N e ur o p s y c hi atr Di s Tr e at. 2 0 0 7; 3: 6 6 9 -7 4. 
P M CI D: P M C 2 6 5 6 3 0 3.  
8.  
T a yl or W D, K u dr a K, Z h a o Z , St eff e n s D C, M a c F all J R. Ci n g ul u m b u n dl e w hit e m att er l e si o n s 
i nfl u e n c e a nti d e pr e s s a nt r e s p o n s e i n l at e-lif e d e pr e s si o n: a pil ot st u d y. J Aff e ct Di s or d. 2 0 1 4; 1 6 2: 8-
1 1. P M CI D: P M C 4 0 3 0 5 3 9.  
9.  
Bl a z er D G. D e pr e s si o n i n l at e lif e: r e vi e w a n d c o m m e nt ar y. J G er o nt ol A Bi ol S ci M e d S ci. 
2 0 0 3; 5 8( 3): 2 4 9 -6 5.  
1 0.  
Al e x o p o ul o s G S, B u c k w alt er K, Oli n J, M arti n e z R, W ai n s c ott C, Kri s h n a n K R. C o m or bi dit y of 
l at e-lif e d e pr e s si o n: a n o p p ort u nit y f or r e s e ar c h i n m e c h a ni s m s a n d tr e at m e nt. Bi ol P s y c hi atr y. 
2 0 0 2; 5 2: 5 4 3 -5 8.  
1 1.  
J a n s s e n J, P ol H E H, S c h n a c k H G, K o k R M, L a m p e I K, d e L e e u w F E, et al. C er e br al v ol u m e 
m e a s ur e m e nt s a n d s u b c orti c al w hit e m att er l e si o n s a n d s h ort -t er m tr e at m e nt r e s p o n s e i n l at e lif e 
d e pr e s si o n. I nt J G eri atr P s y c hi atr y. 2 0 0 7; 2 2: 4 6 8 -7 4.  
1 2.  
Kri s h n a n K R, H a y s J C, G e or g e L K, Bl a z er D G. Si x -m o nt h o ut c o m e s f or M RI -r el at e d v a s c ul ar 
d e pr e s si o n. D e pr e s s A n xi et y. 1 9 9 8; 8: 1 4 2 -6.  
1 3.  
S all o w a y S, B o yl e P A, C orr ei a S, M all o y P F, C a h n -W ei n er D A, S c h n ei d er L, et al. T h e 
r el ati o n s hi p of M RI s u b c orti c al h y p eri nt e n siti e s t o tr e at m e nt r e s p o n s e i n a tri al of s ertr ali n e i n g eri atri c 
d e pr e s s e d o ut p ati e nt s. A m J G eri atr P s y c hi atr y. 2 0 0 2; 1 0: 1 0 7 -1 1.  
1 4.  
S all o w a y S, C orr ei a S, B o yl e P, M all o y P, S c h n ei d er L, L a vr et s k y H, et al. M RI s u b c orti c al 
h y p eri nt e n siti e s i n ol d a n d v er y ol d d e p r e s s e d o ut p ati e nt s: t h e i m p ort a nt r ol e of a g e i n l at e-lif e 
d e pr e s si o n. J N e ur ol S ci. 2 0 0 2; 2 0 3 -2 0 4: 2 2 7 -3 3.  
1 5.  
S n e e d J R, R o o s e S P, K eil p J G, Kri s h n a n K R, Al e x o p o ul o s G S, S a c k ei m H A. R e s p o n s e 
i n hi biti o n pr e di ct s p o or a nti d e pr e s s a nt tr e at m e nt r e s p o n s e i n v er y ol d d e pr e s s e d p ati e nt s. A m J 
G eri atr P s y c hi atr y. 2 0 0 7; 1 5: 5 5 3 -6 3.  
1 6.  
Si m p s o n S, B al d wi n R C, J a c k s o n A, B ur n s A S. I s s u b c orti c al di s e a s e a s s o ci at e d wit h a p o or 
r e s p o n s e t o a nti d e pr e s s a nt s ?  N e ur ol o gi c al, n e ur o p s y c h ol o gi c al a n d n e ur or a di ol o gi c al fi n di n gs i n 
l at e-lif e d e pr e s si o n. P s y c h ol M e d. 1 9 9 8; 2 8: 1 0 1 5-2 6.  
1 7.  
Hi c ki e I, S c ott E, Mit c h ell P, Wil h el m K, A u sti n M P, B e n n ett B. S u b c orti c al h y p eri nt e n siti e s o n 
m a g n eti c r e s o n a n c e i m a gi n g: cli ni c al c orr el at e s a n d pr o g n o sti c si g nifi c a n c e i n p ati e nt s wit h s e v er e  
d e pr e s si o n. Bi ol P s y c hi atr y. 1 9 9 5; 3 7( 3): 1 5 1 -6 0.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
1 8.  
P at a n k ar T F, B al d wi n R, Mitr a D, J effri e s S, S ut cliff e C, B ur n s A, et al. Vir c h o w -R o bi n s p a c e 
dil at ati o n m a y pr e di ct r e si st a n c e t o a nti d e pr e s s a nt m o n ot h er a p y i n el d erl y p ati e nt s wit h d e pr e s si o n. J 
Aff e ct  Di s or d. 2 0 0 7; 9 7: 2 6 5 -7 0.  
1 9.  
G u n ni n g -Di x o n F M, W alt o n M, C h e n g J, A c u n a J, Kli m str a S, Zi m m er m a n M E, et al. M RI 
si g n al h y p eri nt e n siti e s a n d tr e at m e nt r e mi s si o n of g eri atri c d e pr e s si o n. J Aff e ct Di s or d. 
2 0 1 0; 1 2 6( 3): 3 9 5 -4 0 1. P M CI D: P M C 2 9 4 6 9 6 7.  
2 0.  
S n e e d J R, C ul a n g -R ei nli e b M E, Bri c k m a n A M, G u n ni n g -Di x o n F M, J o h n ert L, G ar c o n E, et al. 
M RI si g n al h y p eri nt e n siti e s a n d f ail ur e t o r e mit f oll o wi n g a nti d e pr e s s a nt tr e at m e nt. J Aff e ct Di s or d. 
2 0 1 1; 1 3 5( 1 -3): 3 1 5 -2 0.  
2 1.  
S h eli n e YI, Pi e p er C F, B ar c h D M, W el s h -B o e h m er K,  M c Ki n str y R C, M a c F all J R, et al. 
S u p p ort f or t h e v a s c ul ar d e pr e s si o n h y p ot h e si s i n l at e -lif e d e pr e s si o n: r e s ult s of a 2-sit e, pr o s p e cti v e, 
a nti d e pr e s s a nt tr e at m e nt tri al. Ar c h G e n P s y c hi atr y. 2 0 1 0; 6 7( 3): 2 7 7 -8 5. P M CI D: P M C 2 8 3 8 2 1 0.  
2 2.  
G aff a n D, Wil s o n C R. M e di al t e m p or al a n d pr efr o nt al f u n cti o n: r e c e nt b e h a vi o ur al 
di s c o n n e cti o n st u di e s i n t h e m a c a q u e m o n k e y. C ort e x. 2 0 0 8; 4 4( 8): 9 2 8 -3 5.  
2 3.  
E b eli n g U, Cr a m o n D V. T o p o gr a p h y of t h e u n ci n at e f a s ci cl e a n d a dj a c e nt t e m p or al fi b er tr a ct s. 
A ct a N e ur o c hir ( Wi e n). 1 9 9 2; 1 1 5: 1 4 3 -8.  
2 4.  
Ki er E L, St ai b L H, D a vi s L M, Br o n e n R A. M R i m a gi n g of t h e t e m p or al st e m: a n at o mi c 
di s s e cti o n tr a ct o gr a p h y of t h e u n ci n at e f a s ci c ul u s, i nf eri or o c ci pit ofr o nt al f a s ci c ul u s, a n d M e y er' s l o o p 
of t h e o pti c r a di ati o n. A J N R A m J N e ur or a di ol. 2 0 0 4 ; 2 5( 5): 6 7 7-9 1.  
2 5.  
Z h o n g Y M, Y u ki e M, R o c kl a n d K S. Di sti n cti v e m or p h ol o g y of hi p p o c a m p al C A 1 t er mi n ati o n s i n 
or bit al a n d m e di al fr o nt al c ort e x i n m a c a q u e m o n k e y s. E x p Br ai n R e s. 2 0 0 6; 1 6 9( 4): 5 4 9 -5 3.  
2 6.  
P etri d e s M, P a n d y a D N. Eff er e nt a s s o ci ati o n p at h w a y s f r o m t h e r o str al pr efr o nt al c ort e x i n t h e 
m a c a q u e m o n k e y. J N e ur o s ci. 2 0 0 7; 2 7( 4 3): 1 1 5 7 3 -8 6.  
2 7.  
C at a ni M, T hi e b a ut d e S c h ott e n M. A diff u si o n t e n s or i m a gi n g tr a ct o gr a p h y atl a s f or virt u al i n 
vi v o di s s e cti o n s. C ort e x. 2 0 0 8; 4 4( 8): 1 1 0 5 -3 2.  
2 8.  
Pri c e J L. D efi ni ti o n of t h e or bit al c ort e x i n r el ati o n t o s p e cifi c c o n n e cti o n s wit h li m bi c a n d 
vi s c er al str u ct ur e s a n d ot h er c orti c al r e gi o n s. A n n N Y A c a d S ci. 2 0 0 7; 1 1 2 1: 5 4 -7 1.  
2 9.  
R u dr a uf D, M e ht a S, Gr a b o w s ki T J. Di s c o n n e cti o n' s r e n ai s s a n c e t a k e s s h a p e: F or m al 
i n c or p orati o n i n gr o u p -l e v el l e si o n st u di e s. C ort e x. 2 0 0 8; 4 4( 8): 1 0 8 4-9 6.  
3 0.  
M uf s o n E J, P a n d y a D N. S o m e o b s er v ati o n s o n t h e c o ur s e a n d c o m p o siti o n of t h e ci n g ul u m 
b u n dl e i n t h e r h e s u s m o n k e y. J C o m p N e ur ol. 1 9 8 4; 2 2 5( 1): 3 1 -4 3.  
3 1.  
M orri s R, P a n d y a D N, P etri d e s M. F i b er s y st e m li n ki n g t h e mi d-d or s ol at er al fr o nt al c ort e x wit h 
t h e r etr o s pl e ni al/ pr e s u bi c ul ar r e gi o n i n t h e r h e s u s m o n k e y. J C o m p N e ur ol. 1 9 9 9; 4 0 7( 2): 1 8 3-9 2.  
3 2.  
S e xt o n C E, All a n C L, L e M a s uri er M, M c D er m ott L M, K al u U G, H err m a n n L L, et al. M a g n eti c 
r e s o n a n ce i m a gi n g i n l at e -lif e d e pr e s si o n: m ulti m o d al e x a mi n ati o n of n et w or k di sr u pti o n. Ar c h G e n 
P s y c hi atr y. 2 0 1 2; 6 9( 7): 6 8 0 -9.  
3 3.  
Z h a n g A, L e o w A, Ajil or e O, L a m ar M, Y a n g S, J o s e p h J, et al. Q u a ntit ati v e tr a ct -s p e cifi c 
m e a s ur e s of u n ci n at e a n d ci n g ul u m i n m aj or  d e pr e s si o n u si n g diff u si o n t e n s or i m a gi n g. 
N e ur o p s y c h o p h ar m a c ol o g y. 2 0 1 2; 3 7( 4): 9 5 9 -6 7. P M CI D: P M C 3 2 8 0 6 5 0.  
3 4.  
C h arlt o n R A, L a m ar M, Z h a n g A, Y a n g S, Ajil or e O, K u m ar A. W hit e -m att er tr a ct i nt e grit y i n 
l at e-lif e d e pr e s si o n: a s s o ci ati o n s wit h s e v erit y a n d co g niti o n. P s y c h ol M e d. 2 0 1 3: 1 -1 1.  
3 5.  
G o v e a s J, Xi e C, W u Z, D o u gl a s W ar d B, Li W, Fr a n c z a k M B, et al. N e ur al c orr el at e s of t h e 
i nt er a cti v e r el ati o n s hi p b et w e e n m e m or y d efi cit s a n d d e pr e s si v e s y m pt o m s i n n o n d e m e nt e d el d erl y: 
r e sti n g f M RI st u d y. B e h a v Br ai n R e s. 2 0 1 1; 2 1 9( 2): 2 0 5 -1 2. P M CI D: P M C 3 0 6 2 7 3 3.  
3 6.  
Xi e C, Li W, C h e n G, W ar d B D, Fr a n c z a k M B, J o n e s J L, et al. L at e -lif e d e pr e s si o n, mil d 
c o g niti v e i m p air m e nt a n d hi p p o c a m p al f u n cti o n al n et w or k ar c hit e ct ur e. N e ur oI m a g e Cli ni c al. 
2 0 1 3; 3: 3 1 1 -2 0. P M CI D: P M C 3 8 1 4 9 4 8.  
3 7.  
Al e x o p o ul o s G S, H o pt m a n M J, Y u e n G, K a n ell o p o ul o s D, S eir u p J K, Li m K O, et al. F u n cti o n al 
c o n n e cti vit y i n a p at h y of l at e -lif e d e pr e s si o n: a pr eli mi n ar y st u d y. J Aff e ct Di s or d. 2 0 1 3; 1 4 9( 1-3): 3 9 8 -
4 0 5. P M CI D: P M C 3 6 3 6 1 7 4.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
3 8.  
Al e x o p o ul o s G S, H o pt m a n M J, K a n ell o p o ul o s D, M ur p h y C F, Li m K O, G u n ni n g F M. F u n cti o n al 
c o n n e cti vit y i n t h e c o g niti v e c o ntr ol n et w or k a n d t h e d ef a ult m o d e n et w or k i n l at e -lif e d e pr e s si o n. J 
Aff e ct Di s or d. 2 0 1 2; 1 3 9( 1): 5 6 -6 5. P M CI D: P M C 3 3 4 0 4 7 2.  
3 9.  
K e n n y E R, O' Bri e n J T, C o u si n s D A, R i c h ar d s o n J, T h o m a s A J, Fir b a n k M J, et al. F u n cti o n al 
c o n n e cti vit y i n l at e -lif e d e pr e s si o n u si n g r e sti n g-st at e f u n cti o n al m a g n eti c r e s o n a n c e i m a gi n g. A m J 
G eri atr P s y c hi atr y. 2 0 1 0; 1 8( 7): 6 4 3 -5 1.  
4 0.  
Ai z e n st ei n H J, B utt er s M A, W u M, M a z ur k e wi c z L M, St e n g er V A, Gi a n ar o s P J, et al. Alt er e d 
f u n cti o ni n g of t h e e x e c uti v e c o ntr ol cir c uit i n l at e-lif e d e pr e s si o n: e pi s o di c a n d p er si st e nt p h e n o m e n a. 
A m J G eri atr P s y c hi atr y. 2 0 0 9; 1 7( 1): 3 0 -4 2. P M CI D: P M C 2 6 2 6 1 7 0.  
4 1.  
W u M, A n dr e e s c u C, B utt er s M A, T a m b ur o R, R e y n ol d s C F,  3r d, Ai z e n st ei n H. D ef a ult -m o d e 
n et w or k c o n n e cti vit y a n d w hit e m att er b ur d e n i n l at e -lif e d e pr e s si o n. P s y c hi atr y R e s. 2 0 1 1; 1 9 4( 1): 3 9-
4 6. P M CI D: P M C 3 1 8 9 6 8 5.  
4 2.  
Ai z e n st ei n H J, A n dr e e s c u C, E d el m a n K L, C o c hr a n J L, Pri c e J, B utt er s M A, et al. f M RI 
c orr el at e s  of w hit e m att er h y p eri nt e n siti e s i n l at e -lif e d e pr e s si o n. A m J P s y c hi atr y. 
2 0 1 1; 1 6 8( 1 0): 1 0 7 5 -8 2.  
4 3.  
V e n k atr a m a n V K, Ai z e n st ei n H, G ur al ni k J, N e w m a n A B, Gl y n n N W, T a yl or C, et al. E x e c uti v e 
c o ntr ol f u n cti o n, br ai n a cti v ati o n a n d w hit e m att er h y p eri nt e n si ti e s i n ol d er a d ult s. N e ur oi m a g e. 
2 0 1 0; 4 9( 4): 3 4 3 6 -4 2. P M CI D: P M C 2 8 1 8 5 2 1.  
4 4.  
d e K w a a st e ni et B, R u h e E, C a a n M, Ri v e M, Ol a b arri a g a S, Gr o ef s e m a M, et al. R el ati o n 
b et w e e n str u ct ur al a n d f u n cti o n al c o n n e cti vit y i n m aj or d e pr e s si v e di s or d er. Bi ol P s y c hi atr y. 
2 0 1 3; 7 4( 1): 4 0 -7.  
4 5.  
A n dr e e s c u C, T u d or a s c u D L, B utt er s M A, T a m b ur o E, P at el M, Pri c e J, et al. R e sti n g st at e 
f u n cti o n al c o n n e cti vit y a n d tr e at m e nt r e s p o n s e i n l at e-lif e d e pr e s si o n. P s y c hi atr y R e s. 2 0 1 3; 2 1 4: 3 1 3-
2 1.  
4 6.  
S h eli n e YI, Pri c e J L, Y a n  Z, Mi nt u n M A. R e sti n g -st at e f u n cti o n al M RI i n d e pr e s si o n u n m a s k s 
i n cr e a s e d c o n n e cti vit y b et w e e n n et w or k s vi a t h e d or s al n e x u s. Pr o c N atl A c a d S ci U S A. 
2 0 1 0; 1 0 7( 2 4): 1 1 0 2 0 -5. P M CI D: P M C 2 8 9 0 7 5 4.  
4 7.  
B u c k n er R L, A n dr e w s -H a n n a J R, S c h a ct er D L. T h e br ai n' s d ef a ult n et w or k: a n at o m y, f u n cti o n, 
a n d r el e v a n c e t o di s e a s e. A n n N Y A c a d S ci. 2 0 0 8; 1 1 2 4: 1 -3 8.  
4 8.  
Si e gl e G J, St ei n h a u er S R, T h a s e M E, St e n g er V A, C art er C S. C a n't s h a k e t h at f e eli n g: e v e nt -
r el at e d  f M RI a s s e s s m e nt of s u st ai n e d a m y g d al a a cti vit y i n r e s p o n s e to e m oti o n al i nf or m ati o n i n 
d e pr e s s e d i n di vi d u al s. Bi ol P s y c hi atr y. 2 0 0 2; 5 1: 6 9 3 -7 0 7.  
4 9.  
S a vit z J B, Dr e v et s W C. I m a gi n g p h e n ot y p e s of m aj or d e pr e s si v e di s or d er: g e n eti c c orr el at e s. 
N e ur o s ci e n c e. 2 0 0 9.  
5 0.  
P el u s o M A, Gl a h n D C, M at s u o K, M o n k ul E S, N ajt P, Z a m arri p a F, et al. A m y g d al a 
h y p er a cti v ati o n i n u ntr e at e d d e pr e s s e d i n di vi d u al s. P s y c hi atr y R e s. 2 0 0 9; 1 7 3( 2): 1 5 8 -6 1. P M CI D: 
P M C 2 7 2 0 6 0 3.  
5 1.  
D a n nl o w s ki U, O hr m a n n P, B a u er J, K u g el H, Ar olt V, H ei n d el W, et al. A m y g d al a r e a cti vit y t o 
m a s k e d n e g ati v e f a c e s i s a s s o ci at e d wit h a ut o m ati c j u d g m e nt al bi a s i n m aj or d e pr e s si o n: a 3 T f M RI 
st u d y. J P s y c hi atr N e ur o s ci. 2 0 0 7; 3 2( 6): 4 2 3 -9. P M CI D: P M C 2 0 7 7 3 4 8.  
5 2.  
S u sl o w T, K o nr a d C, K u g el H, R u m st a dt D, Z wit s erl o o d P, S c h o ni n g S, et al. A ut o m ati c m o o d -
c o n gr u e nt a m y g d al a r e s p o n s e s t o m a s k e d f a ci al e x pr e s si o n s i n m aj or d e pr e s si o n. Bi ol P s y c hi atr y. 
2 0 1 0; 6 7( 2): 1 5 5 -6 0.  
5 3.  
R o g er s M A, K a s ai K, K oji M, F u k u d a R, I w a n a mi A, N a k a g o m e K, et al. E x e c uti v e a n d 
pr efr o nt al d y sf u n cti o n i n u ni p ol ar d e pr e s si o n: a r e vi e w of n e ur o p s y c h ol o gi c al a n d i m a gi n g e vi d e n c e. 
N e ur o s ci R e s. 2 0 0 4; 5 0( 1): 1 -1 1.  
5 4.  
B u s h G, L u u P, P o s n er MI. C o g niti v e a n d e m oti o n al i nfl u e n c e s i n a nt eri or ci n g ul at e c ort e x. 
Tr e n d s C o g n S ci. 2 0 0 0; 4( 6): 2 1 5 -2 2.  
5 5.  
V o gt B A, Fi n c h D M, Ol s o n C R. F u n cti o n al h et er o g e n eit y i n ci n g ul at e c ort e x: t h e a nt eri or 
e x e c uti v e a n d p o st eri or e v al u ati v e r e gi o n s. C er e b C ort e x. 1 9 9 2; 2( 6): 4 3 5 -4 3.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
5 6.  
S c h er m ul y I, F ell gi e b el A, W a g n er S, Y a k u s h e v I, St o et er P, S c h mitt R, et al. A s s o ci ati o n 
b et w e e n ci n g ul u m b u n dl e str u ct ur e a n d c o g niti v e p erf or m a n c e: a n o b s er v ati o n al st u d y i n m aj or 
d e pr e s si o n. E ur P s y c hi atr y. 2 0 1 0; 2 5( 6): 3 5 5 -6 0.  
5 7.  
Al e x o p o ul o s G S, Ki o s s e s D N, H e o M, M ur p h y C F, S h a n m u g h a m B, G u n ni n g -Di x o n F. 
E x e c uti v e d y sf u n cti o n a n d t h e c o ur s e of g eri atri c d e pr e s si o n. Bi ol P s y c hi a tr y. 2 0 0 5; 5 8: 2 0 4-1 0.  
5 8.  
S e xt o n C E, M c D er m ott L, K al u U G, H err m a n n L L, Br a dl e y K M, All a n C L, et al. E x pl ori n g t h e 
p att er n a n d n e ur al c orr el at e s of n e ur o p s y c h ol o gi c al i m p air m e nt i n l at e -lif e d e pr e s si o n. P s y c h ol M e d. 
2 0 1 2; 4 2( 6): 1 1 9 5 -2 0 2.  
5 9.  
S a s s o n E, D o ni g e r G M, P a st er n a k O, T arr a s c h R, A s s af Y. W hit e m att er c orr el at e s of 
c o g niti v e d o m ai n s i n n or m al a gi n g wit h diff u si o n t e n s or i m a gi n g. Fr o nti er s i n n e ur o s ci e n c e. 
2 0 1 3; 7: 3 2. P M CI D: P M C 3 5 9 5 5 1 8.  
6 0.  
C h ur c h w ell J C, K e s n er R P. Hi p p o c a m p al -pr efr o nt al d y n a mi c s i n s p ati al w or ki n g m e m or y: 
i nt er a cti o n s a n d i n d e p e n d e nt p ar all el pr o c e s si n g. B e h a v Br ai n R e s. 2 0 1 1; 2 2 5( 2): 3 8 9-9 5. P M CI D: 
P M C 3 5 8 6 9 4 1.  
6 1.  
S h eli n e YI, B ar c h D M, Pri c e J L, R u n dl e M M, V ai s h n a vi S N, S n y d er A Z, et al. T h e d ef a ult 
m o d e n et w or k a n d s elf -r ef er e nti al pr oc e s s e s i n d e pr e s si o n. Pr o c N atl A c a d S ci U S A. 
2 0 0 9; 1 0 6( 6): 1 9 4 2 -7. P M CI D: P M C 2 6 3 1 0 7 8.  
6 2.  
U d di n L Q, K ell y A M, Bi s w al B B, X a vi er C a st ell a n o s F, Mil h a m M P. F u n cti o n al c o n n e cti vit y of 
d ef a ult m o d e n et w or k c o m p o n e nt s: c orr el ati o n, a nti c orr el ati o n, a n d c a u s alit y . H u m Br ai n M a p p. 
2 0 0 9; 3 0( 2): 6 2 5 -3 7.  
6 3.  
Gr ei ci u s M D, Fl or e s B H, M e n o n V, Gl o v er G H, S ol v a s o n H B, K e n n a H, et al. R e sti n g -st at e 
f u n cti o n al c o n n e cti vit y i n m aj or d e pr e s si o n: a b n or m all y i n cr e a s e d c o ntri b uti o n s fr o m s u b g e n u al 
ci n g ul at e c ort e x a n d t h al a m u s. Bi ol P s y c hi atr y. 2 0 0 7; 6 2( 5): 4 2 9 -3 7. P M CI D: P M C 2 0 0 1 2 4 4.  
6 4.  
Z h o u Y, Y u C, Z h e n g H, Li u Y, S o n g M, Qi n W, et al. I n cr e a s e d n e ur al r e s o ur c e s r e cr uit m e nt 
i n t h e i ntri n si c or g a ni z ati o n i n m aj or d e pr e s si o n. J Aff e ct Di s or d. 2 0 1 0; 1 2 1( 3): 2 2 0-3 0.  
6 5.  
Pi z z a g alli D A. F r o nt o ci n g ul at e D y sf u n cti o n i n D e pr e s si o n: T o w ar d Bi o m ar k er s of Tr e at m e nt 
R e s p o n s e. N e ur o p s y c h o p h ar m a c ol o g y. 2 0 1 1; 3 6: 1 8 3 -2 0 6. P M CI D: P M C P M C 3 0 3 6 9 5 2.  
6 6.  
Z h u X, W a n g X, Xi a o J, Li a o J, Z h o n g M, W a n g W, et al. E vi d e n c e of a di s s o ci ati o n p att er n i n 
r e sti n g-st at e d ef a ult m o d e n et w or k c o n n e cti vit y i n fir st -e pi s o d e, tr e at m e nt -n ai v e m aj or d e pr e s si o n 
p ati e nt s. Bi ol P s y c hi atr y. 2 0 1 2; 7 1( 7): 6 1 1 -7.  
6 7.  
T ei p el S J, B o k d e A L, M ei n dl T, A m ar o E, Jr., S ol d n er J, R ei s er M F, et al. W hit e m att er 
mi cr o str u ct ur e u n d erl yi n g d ef a ult  m o d e n et w or k c o n n e cti vit y i n t h e h u m a n br ai n. N e ur oi m a g e. 
2 0 1 0; 4 9( 3): 2 0 2 1 -3 2.  
6 8.  
v a n d e n H e u v el M, M a n dl R, L ui gj e s J, H ul s h off P ol H. Mi cr o str u ct ur al or g a ni z ati o n of t h e 
ci n g ul u m tr a ct a n d t h e l e v el of d ef a ult m o d e f u n cti o n al c o n n e cti vit y. J N e ur o s ci. 2 0 0 8; 2 8( 4 3): 1 0 8 4 4 -
5 1.  
6 9.  
W ei s s m a n D H, R o b ert s K C, Vi s s c h er K M, W ol d orff M G. T h e n e ur al b a s e s of m o m e nt ar y 
l a p s e s i n att e nti o n. N at N e ur o s ci. 2 0 0 6; 9( 7): 9 7 1-8.  
7 0.  
K a nt ar ci K, S e nj e m M L, A v ul a R, Z h a n g B, S a mi k o gl u A R, W ei g a n d S D, et al. Diff u si o n t e n s or 
i m agi n g a n d c o g niti v e f u n cti o n i n ol d er a d ult s wit h n o d e m e nti a. N e ur ol o g y. 2 0 1 1; 7 7( 1): 2 6 -3 4. 
P M CI D: P M C 3 1 2 7 3 3 3.  
7 1.  
G or d o n E M, L e e P S, M ai s o g J M, F o s s -F ei g J, Billi n gt o n M E, V a n m et er J, et al. Str e n gt h of 
d ef a ult m o d e r e sti n g -st at e c o n n e cti vit y r el at e s t o w h it e m att er i nt e grit y i n c hil dr e n. D e v S ci. 
2 0 1 1; 1 4( 4): 7 3 8 -5 1. P M CI D: P M C 3 1 1 7 4 4 0.  
7 2.  
S a s s o n E, D o ni g er G M, P a st er n a k O, T arr a s c h R, A s s af Y. Str u ct ur al c orr el at e s of c o g niti v e 
d o m ai n s i n n or m al a gi n g wit h diff u si o n t e n s or i m a gi n g. Br ai n Str u ct F u n ct. 2 0 1 2; 2 1 7( 2): 5 0 3 -1 5.  
7 3.  
D u eri n g M, G o ni k M, M ali k R, Zi er e n N, R e y e s S, J o u v e nt E, et al. I d e ntifi c ati o n of a str at e gi c 
br ai n n et w or k u n d erl yi n g pr o c e s si n g s p e e d d efi cit s i n v a s c ul ar c o g niti v e i m p air m e nt. N e ur oi m a g e. 
2 0 1 2; 6 6 C: 1 7 7 -8 3.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
7 4.  
Gr ei ci u s M D, S u p e k ar K, M e n o n V, D o u g h ert y R F. R e sti n g -st at e f u n cti o n al c o n n e cti vit y 
r efl e ct s str u ct ur al c o n n e cti vit y i n t h e d ef a ult m o d e n et w or k. C er e b C ort e x. 2 0 0 9; 1 9( 1): 7 2-8. P M CI D: 
P M C 2 6 0 5 1 7 2.  
7 5.  
B ai F, Z h a n g Z, W at s o n D R, Y u H, S hi Y, Y u a n Y, et al. A b n or m al f u n c ti o n al c o n n e cti vit y of 
hi p p o c a m p u s d uri n g e pi s o di c m e m or y r etri e v al pr o c e s si n g n et w or k i n a m n e sti c mil d c o g niti v e 
i m p air m e nt. Bi ol P s y c hi atr y. 2 0 0 9; 6 5( 1 1): 9 5 1-8.  
7 6.  
S c h ott B H, W u st e n b er g T, Wi m b er M, F e n k er D B, Zi er h ut K C, S ei d e n b e c h er CI, et al. T h e 
r el ati o n s hi p b et w e e n l e v el of pr o c e s si n g a n d hi p p o c a m p al-c orti c al f u n cti o n al c o n n e cti vit y d uri n g 
e pi s o di c m e m or y f or m ati o n i n h u m a n s. H u m Br ai n M a p p. 2 0 1 1.  
7 7.  
S e sti eri C, C or b ett a M, R o m a ni G L, S h ul m a n G L. E pi s o di c m e m or y r etri e v al, p ari et al c ort e x, 
a n d t h e d ef a ult m o d e n et w or k: f u n cti o n al a n d t o p o gr a p hi c a n al y s e s. J N e ur o s ci. 2 0 1 1; 3 1( 1 2): 4 4 0 7 -
2 0. P M CI D: P M C 3 0 9 8 0 4 0.  
7 8.  
B u c h s b a u m M S, W u J, Si e g el B V, H a c k ett E, Tr e n ar y M, A b el L, et al. Eff e ct of s ertr ali n e o n 
r e gi o n al m et a b oli c r at e i n p ati e nt s wit h aff e cti v e di s or d er. Bi ol P s y c hi atr y. 1 9 9 7; 4 1: 1 5 -2 2.  
7 9.  
Dr e v et s W C, B o g er s W, R ai c hl e M E. F u n cti o n al a n at o mi c al c orr el at e s of a nti d e pr e s s a nt dr u g 
tr e at m e nt a s s e s s e d u si n g P E T m e a s ur e s of r e gi o n al gl u c o s e m et a b oli s m. E ur 
N e ur o p s y c h o p h ar m a c ol. 2 0 0 2; 1 2: 5 2 7 -4 4.  
8 0.  
M a y b er g H S, Br a n n a n S K, T e k ell J L, Sil v a A, M a h uri n R K, M c Gi ni s S, et al. R e gi o n al 
m et a b oli c eff e ct s of fl u o x eti n e i n m aj or d e pr e s si o n: s eri al c h a n g e s a n d r el ati o n s hi p t o cli n c al 
r e s p o n s e. Bi ol P s y c hi atr y. 2 0 0 0; 4 8: 8 3 0-4 3.  
8 1.  
K e n n e d y S H, E v a n s K R, Kr u g er S, M a y b er g H S, M e y er J H, M c C a n n S, et al. C h a n g e s i n 
r e gi o n al br ai n gl u c o s e m et a b oli s m m e a s ur e d wit h p o sitr o n e mi s si o n t o m o gr a p h y aft er p ar o x eti n e 
tr e at m e nt of m aj or d e pr e s s si o n. A m J P s y c hi atr y. 2 0 0 1; 1 5 8: 8 9 9-9 0 5.  
8 2.  
C arl s o n P J, Si n g h J B, Z ar at e C A, Jr., Dr e v et s W C, M a nji H K. N e ur al cir c uitr y a n d 
n e ur o pl a sti cit y i n m o o d di s or d er s: i n si g ht s f or n o v el t h er a p e uti c t ar g et s. N e ur o R x. 2 0 0 6; 3( 1): 2 2 -4 1.  
8 3.  
M c C a b e C, Mi s h or Z. A nti d e pr e s s a nt m e di c ati o n s r e d u c e s u b c orti c al -c orti c al r e sti n g -st at e 
f u n cti o n al c o n n e cti vit y i n h e alt h y v ol u nt e er s. N e ur oi m a g e. 2 0 1 1; 5 7( 4): 1 3 1 7-2 3. P M CI D: 
P M C 3 1 4 1 1 0 9.  
8 4.  
Li si e c k a D, M ei s e n z a hl E, S c h e u er e c k er J, S c h o e pf V, W hitt y P, C h a n e y A, et al. N e ur al 
c orr el at e s of tr e at m e nt o ut c o m e i n m aj or d e pr e s si o n. I nt J N e ur o p s y c h o p h ar m a c ol. 2 0 1 1; 1 4( 4 ): 5 2 1-
3 4.  
8 5.  
W a g n er G, K o c h K, S c h a c ht z a b el C, S o b a n s ki T, R ei c h e n b a c h J R, S a u er H, et al. Diff er e nti al 
eff e ct s of s er ot o n er gi c a n d n or a dr e n er gi c a nti d e pr e s s a nt s o n br ai n a cti vit y d uri n g a c o g niti v e c o ntr ol 
t a s k a n d n e ur of u n cti o n al pr e di cti o n of tr e at m e nt o ut c o m e i n p ati e nt s wit h d e pr e s si o n. J P s y c hi atr 
N e ur o s ci. 2 0 1 0; 3 5( 4): 2 4 7 -5 7. P M CI D: P M C 2 8 9 5 1 5 5.  
8 6.  
Br u hl A B, J a n c k e L, H er wi g U. Diff er e nti al m o d ul ati o n of e m oti o n pr o c e s si n g br ai n r e gi o n s b y 
n or a dr e n er gi c a n d s er ot o n er gi c a nti d e pr e s s a nt s. P s y c h o p h ar m a c ol o g y ( B erl). 2 0 1 1; 2 1 6( 3): 3 8 9 -9 9.  
8 7.  
Z h o u F C, T a o -C h e n g J H, S e g u L, P at el T, W a n g Y. S er ot o ni n tr a n s p ort er s ar e l o c at e d o n t h e 
a x o n s b e y o n d t h e s y n a pti c j u n cti o n s: a n at o mi c al a n d f u n cti o n al e vi d e n c e. Br ai n R e s. 1 9 9 8; 8 0 5( 1 -
2): 2 4 1 -5 4.  
8 8.  
Bi v er F, Wi kl er D,  L ot str a F, D a m h a ut P, G ol d m a n S, M e n dl e wi c z J. S er ot o ni n 5 -H T 2 r e c e pt or 
i m a gi n g i n m aj or d e pr e s si o n: f o c al c h a n g e s i n or bit o-i n s ul ar c ort e x. Br J P s y c hi atr y. 1 9 9 7; 1 7 1: 4 4 4-8.  
8 9.  
M o s e s -K ol k o E L, Pri c e J C, T h a s e M E, M elt z er C C, K u pf er D J, M at hi s C A, et al. M e a s ur e m e nt 
of 5 -H T 1 A r e c e pt or bi n di n g i n d e pr e s s e d a d ult s b ef or e a n d aft er a nti d e pr e s s a nt dr u g tr e at m e nt u si n g 
p o sitr o n e mi s si o n t o m o gr a p h y a n d [ 1 1 C] W A Y -1 0 0 6 3 5. S y n a p s e. 2 0 0 7; 6 1( 7): 5 2 3 -3 0.  
9 0.  
Dr e v et s W C, T h a s e M E, M o s e s -K ol k o E L, Pri c e J, Fr a n k E, K u pf er  D J, et al. S er ot o ni n -1 A 
r e c e pt or i m a gi n g i n r e c urr e nt d e pr e s si o n: r e pli c ati o n a n d lit er at ur e r e vi e w. N u cl e ar m e di ci n e a n d 
bi ol o g y. 2 0 0 7; 3 4( 7): 8 6 5 -7 7. P M CI D: P M C 2 7 0 2 7 1 5.  
9 1.  
F o ot e S L, M orri s o n J H. E xtr at h al a mi c m o d ul ati o n of c orti c al f u n cti o n. A n n u R e v N e u r o s ci. 
1 9 8 7; 1 0: 6 7 -9 5.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
9 2.  
H ari n g J H, D a vi s J N. Diff er e nti al di stri b uti o n of l o c u s c o er ul e u s pr oj e cti o n s t o t h e hi p p o c a m p al 
f or m ati o n: a n at o mi c al a n d bi o c h e mi c al e vi d e n c e. Br ai n R e s. 1 9 8 5; 3 2 5( 1-2): 3 6 6 -9.  
9 3.  
S ar a S J. T h e l o c u s c o er ul e u s a n d n or a dr e n er gi c m o d ul ati o n of c o g niti o n. N at R e v N e ur o s ci. 
2 0 0 9; 1 0( 3): 2 1 1 -2 3.  
9 4.  
All m a n J M, H a k e e m A, Er wi n J M, Ni m c hi n s k y E, H of P. T h e a nt eri or ci n g ul at e c ort e x. T h e 
e v ol uti o n of a n i nt erf a c e b et w e e n e m oti o n a n d c o g niti o n. A n n N Y A c a d S ci. 2 0 0 1; 9 3 5: 1 0 7 -1 7.  
9 5.  
Bj or kl u n d  A, D u n n ett S B. D o p a mi n e n e ur o n s y st e m s i n t h e br ai n: a n u p d at e. Tr e n d s N e ur o s ci. 
2 0 0 7; 3 0( 5): 1 9 4 -2 0 2.  
9 6.  
S ar a S J. T h e l o c u s c o er ul e u s a n d n or a dr e n er gi c m o d ul ati o n of c o g niti o n. N at R e v N e ur o s ci. 
2 0 0 9; 1 0( 3): 2 1 1 -2 3.  
9 7.  
R e e p R. R el ati o n s hi p b et w e e n pr efr o nt al a n d li m bi c c ort e x: a c o m p ar ati v e a n at o mi c al r e vi e w. 
Br ai n, b e h a vi or a n d e v ol uti o n. 1 9 8 4; 2 5( 1): 5 -8 0.  
9 8.  
D u nl o p B W, N e m er off C B. T h e r ol e of d o p a mi n e i n t h e p at h o p h y si ol o g y of d e pr e s si o n. Ar c h 
G e n P s y c hi atr y. 2 0 0 7; 6 4( 3): 3 2 7 -3 7.  
9 9.  
S h e e h a n D V, L e cr u bi er Y, S h e e h a n K H, A m ori m P, J a n a v s J, W eill er E, et al. T h e Mi ni -
I nt er n ati o n al N e ur o p s y c hi atri c I n v e nt or y ( M.I. N.I.): t h e d e v el o p m e nt a n d v ali d ati o n of a str u ct ur e d 
di a g n o sti c i nt er vi e w f or D S M -I V a n d I C D-1 0. J Cli n P s y c hi atr y. 1 9 9 8; S u p pl 2 0: 2 2 -3 3.  
1 0 0.  S h e e h a n D V, L e cr u bi er Y, S h e e h a n K H, J a n a v s J, W eill er E, K e s ki n er A, et al. T h e v ali dit y of 
t h e Mi ni I nt er n ati o n al N e ur o p s y c hi atri c I nt er vi e w ( MI NI) a c c or di n g t o t h e S CI D-P a n d it s r eli a bilit y. E ur 
P s y c hi atr y. 1 9 9 7; 5: 2 3 2 -4 1.  
1 0 1.  M o nt g o m er y S A, A s b er g M. A n e w d e pr e s si o n s c al e d e si g n e d t o b e s e n siti v e t o c h a n g e. Br J 
P s y c hi atr y. 1 9 7 9; 1 3 4: 3 8 2 -9.  
1 0 2.  R u s h A J, Tri v e di M H, I br a hi m H M, C ar m o d y T J, Ar n o w B, Kl ei n D N, et al. T h e 1 6 -It e m Q ui c k 
I n v e nt or y of D e pr e s si v e S y m pt o m at ol o g y ( QI D S), cli ni ci a n r ati n g ( QI D S-C), a n d s elf -r e p ort ( QI D S-
S R): a p s y c h o m etri c e v al u ati o n i n p ati e nt s wit h c hr o ni c m aj or d e pr e s si o n. Bi ol P s y c hi atr y. 
2 0 0 3; 5 4( 5): 5 7 3 -8 3.  
1 0 3.  R u s h A J, B er n st ei n I H, Tri v e di M H, C ar m o d y T J, Wi s ni e w s ki S, M u n dt J C, et al. A n e v al u ati o n 
of t h e q ui c k i n v e nt or y of d e pr e s si v e s y m pt o m at ol o g y a n d t h e h a milt o n r ati n g s c al e f or d e pr e s si o n: a 
s e q u e n c e d tr e at m e nt alt er n ati v e s t o r eli e v e d e pr e s si o n tri al r e p ort. Bi ol P s y c hi atr y. 2 0 0 6; 5 9( 6): 4 9 3 -
5 0 1.  
1 0 4.  Tri v e di M H, R u s h A J, I br a hi m H M, C ar m o d y T J, Bi g g s M M, S u p p e s T, et al. T h e I n v e nt or y of 
D e pr e s si v e S y m pt o m at ol o g y, Cli ni ci a n R ati n g (I D S -C) a n d S elf -R e p ort (I D S -S R), a n d t h e Q ui c k 
I n v e nt or y of D e pr e s si v e S y m pt o m at ol o g y, Cli ni ci a n R ati n g ( QI D S-C) a n d S elf -R e p ort ( QI D S -S R) i n 
p u bli c s e ct or p ati e nt s wit h m o o d di s or d er s: a p s y c h o m etri c e v al u ati o n. P s y c h ol M e d. 2 0 0 4; 3 4( 1): 7 3 -
8 2.  
1 0 5.  K ell er M B, L a v ori P W, Fri e d m a n D S, Ni el s e n E, E n di c ott J, M c D o n al d -S c ott P, et al. T h e 
l o n git u di n al i nt er v al f oll o w-u p e v al u ati o n. A c o m pr e h e n si v e m et h o d f or a s s e s si n g o ut c o m e i n 
pr o s p e cti v e l o n git u di n al st u di e s. Ar c h G e n P s y c hi atr y. 1 9 8 7; 4 4: 5 4 0 -8.  
1 0 6.  S a c k ei m H A, Pr u di c J, D e v a n a n d D P, D e ci n a P, K err B, M alit z S. T h e i m p a ct of m e di c ati o n 
r e si st a n c e a n d c o nti n u ati o n p h ar m a c ot h er a p y o n r el a p s e f oll o wi n g r e s p o n s e t o el e ctr o c o n v ul si v e 
t h er a p y i n m aj or d e pr e s si o n. J Cli n P s y c h o p h ar m a c ol. 1 9 9 0; 1 0: 9 6-1 0 4.  
1 0 7.  M ari n R S, Bi e dr z y c ki R C, Firi n ci o g ull ari S. R eli a bilit y a n d v ali dit y of t h e A p at h y E v al u ati o n 
S c al e. P s y c hi atr y R e s. 1 9 9 1; 3 8( 2): 1 4 3 -6 2.  
1 0 8.  M ari n R S, Firi n ci o g ull ari S, Bi e dr z y c ki R C. T h e s o ur c e s of c o n v er g e n c e b et w e e n m e a s ur e s of 
a p at h y a n d d e pr e s si o n. J Aff e ct Di s or d. 1 9 9 3; 2 8( 1): 7 -1 4.  
1 0 9.  Mill er M D, P ar a di s C F, H o u c k P R, M a z u m d ar S, St a c k J A, Rif ai A H, et al. R ati n g c hr o ni c 
m e di c al ill n e s s b ur d e n i n g er o p s y c hi atri c pr a cti c e a n d r e s e a r c h: a p pli c ati o n of t h e C u m ul ati v e Ill n e s s 
R ati n g S c al e. P s y c hi atr y R e s. 1 9 9 2; 4 1: 2 3 7 -4 8.  
1 1 0.  W olf P A, D' A g o sti n o R B, B el a n g er A J, K a n n el W B. Pr o b a bilit y of str o k e: A ri s k pr ofil e fr o m t h e 
Fr a mi n g h a m St u d y. Str o k e. 1 9 9 1; 2 2: 3 1 2 -8.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
1 1 1.  Wi s ni e w s ki S R, R u s h A J, B al a s u br a m a ni G K, Tri v e di M H, Ni er e n b er g A A. S elf -r at e d gl o b al 
m e a s ur e of t h e fr e q u e n c y, i nt e n sit y, a n d b ur d e n of si d e eff e ct s. J o ur n al of P s y c hi atri c Pr a cti c e. 
2 0 0 6; 1 2( 2): 7 1 -9.  
1 1 2.  M ori s k y D E, Gr e e n L W, L e vi n e D M. C o n c urr e nt a n d pr e di cti v e v ali dit y of  a s elf -r e p ort e d 
m e a s ur e of m e di c ati o n a d h er e n c e. M e d C ar e. 1 9 8 6; 2 4( 1): 6 7 -7 4.  
1 1 3.  S h eli n e YI, B ar c h D M, G ar ci a K, G er si n g K, Pi p er C, W el s h -B o h m er K A, et al. C o g niti v e 
f u n cti o n i n l at e lif e d e pr e s si o n: r el ati o n s hi p s t o d e pr e s si o n s e v erit y, c er e br o v a s c ul ar ri s k f a ct or s a n d 
pr o c e s si n g s p e e d. Bi ol P s y c hi atr y. 2 0 0 6; 6 0: 5 8 -6 5.  
1 1 4.  Al e x o p o ul o s G S, M e y er s B S, Y o u n g R C, K al a y a m B, K a k u m a T, G a bri ell e M, et al. E x e c uti v e 
d y sf u n cti o n a n d l o n g -t er m o ut c o m e s of g eri atri c d e pr e s si o n. Ar c h G e n P s y c hi atr y. 2 0 0 0; 5 7: 2 8 5-9 0 . 
1 1 5.  C arr a s c o J L, S a n d n er C. Cli ni c al eff e ct s of p h ar m a c ol o gi c al v ari ati o n s i n s el e cti v e s er ot o ni n 
r e u pt a k e i n hi bit or s: a n o v er vi e w. I nt J Cli n Pr a ct. 2 0 0 5; 5 9( 1 2): 1 4 2 8-3 4.  
1 1 6.  F a v a M, R u s h A J, Tri v e di M H, Ni er e n b er g A A, T h a s e M E, S a c k ei m H A, et al. B a c k gr o u n d a n d 
r ati o n al e f or t h e s e q u e n c e d tr e at m e nt alt er n ati v e s t o r eli e v e d e pr e s si o n ( S T A R* D) st u d y. P s y c hi atr 
Cli n N ort h A m. 2 0 0 3; 2 6: 4 5 7 -9 4.  
1 1 7.  St a hl S M, Pr a d k o J F, H ai g ht B R, M o d ell J G, R o c k ett C B, L e ar n e d -C o u g hli n S. A R e vi e w of t h e 
N e ur o p h ar m a c ol o g y o f B u pr o pi o n, a D u al N or e pi n e p hri n e a n d D o p a mi n e R e u pt a k e I n hi bit or. Pri m 
C ar e C o m p a ni o n J Cli n P s y c hi atr y. 2 0 0 4; 6( 4): 1 5 9 -6 6. P M CI D: P M C 5 1 4 8 4 2.  
1 1 8.  K a n e J M, C ol e K, S ar a nt a k o s S, H o w ar d A, B or e n st ei n M. S af et y a n d effi c a c y of b u pr o pi o n i n 
el d erl y p ati e nt s:  pr eli mi n ar y o b s er v ati o n s. J Cli n P s y c hi atr y. 1 9 8 3; 4 4: 1 3 4 -6.  
1 1 9.  St eff e n s D C, D or ai s w a m y P M, M c Q u oi d D R. B u pr o pi o n S R i n t h e n at ur ali sti c tr e at m e nt of 
el d erl y p ati e nt s wit h m aj or d e pr e s si o n. I nt J G eri atr P s y c hi atr y. 2 0 0 1; 1 6: 8 6 2 -5.  
1 2 0.  D or ai s w a m y P M, K h a n Z M, D o n a h u e R M, Ri c h ar d N E. Q u alit y of lif e i n g eri atri c d e pr e s si o n: a 
c o m p ari s o n of r e mitt er s, p arti al r e s p o n d er s, a n d n o nr e s p o n d er s. A m J G eri atr P s y c hi atr y. 
2 0 0 1; 9( 4): 4 2 3 -8.  
1 2 1.  W h yt e E M, B a si n s ki J, F ar hi P, D e w M A, B e gl e y A, M ul s a nt B H, et al. G eri atri c d e pr e s si o n 
tr e at m e nt i n n o nr e s p o n d er s t o s el e cti v e s er ot o ni n r e u pt a k e i n hi bit or s. J Cli n P s y c hi atr y. 
2 0 0 4; 6 5: 1 6 3 4 -4 1.  
1 2 2.  D e w M A, W h yt e E M, L e n z e E J, H o u c k P R, M ul s a nt B H, P oll o c k B G, et al. R e c o v er y fr o m 
m aj or d e pr e s si o n i n ol d er a d ult s r e c ei vi n g a u g m e nt ati o n of a nti d e pr e s s a nt p h ar m a c ot h er a p y. A m J 
P s y c hi atr y. 2 0 0 7; 1 6 4( 6): 8 9 2 -9.  
1 2 3.  Tri v e di M H, F a v a M, Wi s ni e w s ki S R, T h a s e M E, Q uit ki n F, W ar d e n D, et al. M e di c ati o n 
a u g m e nt ati o n aft er t h e f ail ur e of S S RI s f or d e pr e s si o n. N E n gl J M e d. 2 0 0 6; 3 5 4( 1 2): 1 2 4 3 -5 2.  
1 2 4.  R u s h A J, Tri v e di M H, Wi s ni e w s ki S R, St e w art J W, Ni er e n b er g A A, T h a s e M E, et al. 
B u pr o pi o n -S R, s ertr ali n e, or v e nl af a xi n e -X R aft er f ail ur e of S S RI s f or d e pr e s si o n. N E n gl J M e d. 
2 0 0 6; 3 5 4( 1 2): 1 2 3 1 -4 2.  
1 2 5.  G a y n e s B N, D u s et zi n a S B, Elli s A R, H a n s e n R A, F arl e y J F, Mill er W C, et al. Tr e ati n g 
d e pr e s si o n aft er i niti al tr e at m e nt f ail ur e: dir e ctl y c o m p ari n g s wit c h a n d a u g m e nti n g str at e gi e s i n 
S T A R* D. J Cli n P s y c h o p h ar m a c ol. 2 0 1 2; 3 2( 1): 1 1 4 -9.  
1 2 6.  S c h mi dt P, G a s er C, Ar si c M, B u c k D, F or s c hl er A, B ert h el e A, et al. A n a ut o m at e d t o ol f or 
d et e cti o n of F L AI R -h y p eri nt e n s e w hit e -m att er l e si o n s i n M ulti pl e S cl er o si s. N e ur oi m a g e. 
2 0 1 2; 5 9( 4): 3 7 7 4 -8 3.  
1 2 7.  S o b el M E. A s y m pt oti c i nt er v al s f or i n dir e ct eff e ct s i n str u ct ur al e q u ati o n s m o d el s. I n: L ei n h art 
S, e dit or. S o ci ol o gi c al M et h o d ol o g y 1 9 8 2. p. 2 9 0 -3 1 2.  
1 2 8.  Pr e a c h er K J, H a y e s A F. A s y m pt oti c a n d r e s a m pli n g str at e gi e s f or a s s e s si n g a n d c o m p ari n g 
i n dir e ct eff e ct s i n m ulti pl e m e di at or m o d el s. B e h a v R e s M et h o d s. 2 0 0 8; 4 0( 3): 8 7 9-9 1.  
1 2 9.  St eff e n s D C, T a yl or W D, D e n n y K L,  B er g m a n S R, W a n g L. Str u ct ur al i nt e grit y of t h e u n ci n at e 
f a s ci c ul u s a n d r e sti n g st at e f u n cti o n al c o n n e cti vit y of t h e v e ntr al pr efr o nt al c ort e x i n l at e lif e 
d e pr e s si o n. P L o S O N E. 2 0 1 1; 6( 7): e 2 2 6 9 7. P M CI D: P M C 3 1 4 2 1 8 5.  
1 3 0.  P A S S U s er' s G ui d e. K a y s vill e, Ut a h:  N C S S; 2 0 0 0.  


Pr ot o c ol V er si o n: 2. 0  
Pr ot o c ol D at e: 0 4/ 1 0/ 2 0 2 0  
 
 

ICF_001.pdf: 
Title: Connectivity Affecting the Antidepressant Response (CAARE) 
Consent form for depressed participants 
 
Clinicaltrials.gov Identifier: NCT02332291 
 
 
NIH Grant: R01 MH102246 
NIH Grant Title: Neural Connectivity Affecting the Antidepressant Response: Testing a Lesion Model 
 
Document Date: 11/7/2019 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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This informed consent applies to depressed adults age 60 or above 
 
 
Name of participant: _________________________________________________________ Age: ___________ 
 
The following is given to you to tell you about this research study.  Please read this form with care and 
ask any questions you may have about this study.  Your questions will be answered.  Also, you will be 
given a copy of this consent form.   
 
You do not have to be in this research study. You may choose not to be in this study and get other treatments 
without changing your healthcare, services or other rights.   You can stop being in this study at any time.  If we 
learn something new that may affect the risks or benefits of this study, you will be told so that you can decide 
whether or not you still want to be in this study.   Your medical record will contain a note saying you are in a 
research study.  Anyone you authorize to receive your medical record will also get this note. 
 
 
     
1. What is the purpose of this study?  
 
You are being asked to take part in this research study because you have depression and are 
age 60 years or older.  We have known for a long time that individuals with depression respond 
differently to antidepressant medications.  For example, one individual may do very well with a 
given medication, while another individual may not respond at all.  There is currently no way to 
determine how an individual will respond to any given medication. 
 
We think that differences in how people respond to medication are related to differences in brain 
function and connections between brain regions.  When someone is depressed, we see on brain 
imaging that their brain may work differently than people who are not depressed.  When 
depression improves with treatment, brain function appears to become normal.   We think that 
individual differences in brain function and brain connections during depression may contribute 
to why people respond differently to antidepressant medications. 
 
The purpose of the study is to better understand the relationship between brain function and 
brain connectivity and how adults over the age of 60 years respond to antidepressant 
medications.   For this study, we will examine two different antidepressant medications that have 
different ways of working.   We will examine escitalopram, also known as Lexapro, and 
bupropion, also know as Wellbutrin.  Both medications are commercially available and approved 
by the U.S. Food and Drug Administration for the treatment of depression. We plan to enroll up 
to 200 depressed individuals and 55 non-depressed controls for this study over five years. 
 
 
 
 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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2. What will happen and how long will you be in the study? 
   
If you agree to be in this study, you will first be asked to sign and date this consent form.  The 
study has two phases.  Phase 1 will last at least 8 weeks, and Phase 2 will last an additional 9 
weeks. Before starting the study medication, you will have a clinical assessment, memory 
testing, and a brain MRI scan. If you are currently depressed and taking an antidepressant, we 
will need to stop it before you can start the study medication.  
 
Phase 1 ‘Assessment Visit’: During the initial visit, you will meet both with the study 
coordinator and the study doctor.  Your medical and psychiatric history will be carefully reviewed 
to make sure that you are eligible for the study.  Additionally, we will assess your current 
depression symptoms as well as your current and past medication use.  You do not have to 
answer any questions you do not feel comfortable answering. The interview with the study 
coordinator will take about 90 minutes.  Your visit with the study doctor will take about an hour. 
 
For your safety, you must tell your study doctor about all the medications you are taking, 
including over-the-counter drugs and herbals, before you start the study and before taking any 
new medications while you are on the study. 
 
As part of this visit, we will carefully evaluate you to determine if you have any metal in your 
body that could stop you from having the MRI.  If you have had surgeries that used implanted 
metal objects, we will need to request medical records to assure your safety before you could 
proceed to MRI.  If you have had surgeries where records are not available and you do not think 
those surgeries included metal, we may ask you to have an x-ray of that part of your body to 
make sure there is no metal in that site. 
 
During this visit, you will also have an option to complete a “mock” MRI scan.  Although no 
actual scan is taken, you will be able to experience the process (getting on and off the table, 
being inside the scanning tube, hearing the sounds the machine produces during a scan) to 
make sure you are comfortable with having an MRI scan.  
 
Stopping Current Antidepressants: If eligible and willing to participate, and you are taking a 
medication for depression, your study doctor will work with you on a plan to safely stop that 
medication.  He will develop a schedule that will slowly reduce and stop your current 
antidepressant.  Depending on your individual medical history, this may take several days or a 
few weeks.  During this time, we will speak to you at least weekly by telephone to make sure 
that you are not having any problems coming off the medication and that your depression is not 
worsening.  If you want to come for in-person visits, we can do this as well.  Once you are off 
your current antidepressant, you will return for the Phase 1 ‘Testing Visit’. 
    


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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Phase 1 ‘Baseline Visit’: This will be an in-person visit with your study doctor who will again 
assess your depression symptoms. During this visit, you will complete the memory testing and 
MRI scan. This visit can last about half of the day. Due to scheduling, we may need to spread 
these procedures over two days. 
 
Memory Testing:  We will ask you to complete some tasks that measure your memory, 
concentration, and problem-solving abilities.  Some of these will be done using pencil-and-paper 
while other tests will be done on a computer.  The memory testing will take about two hours. 
 
MRI: You will complete a brain scan using Magnetic Resonance Imaging (MRI). This will be a 
one-hour long session. An MRI scan is taken in a large machine that is shaped like a tunnel. 
This scan does not use x-rays. Instead, they use a strong magnet and radio waves, like those 
used in an AM/FM radio, to make pictures of your body. 
 
You may not be able to have this scan if you have a device in your body, such as aneurysm 
clips in the brain, heart pacemakers or defibrillators, and cochlear (inner ear) implants. Also, you 
may not be able to have this scan if you have iron-based tattoos or pieces of metal (bullet, BB, 
shrapnel) close to or in an important organ (such as the eye).  If we determine you cannot safely 
complete the MRI, we will withdraw you from the study. 
 
Certain metal objects like watches, credit cards, hairpins, writing pens, etc. may be damaged by 
the machine or may be pulled away from the body when you are getting the scan. Also, metal 
can sometimes cause poor pictures if it is close to the part of the body being scanned. For these 
reasons, you will be asked to remove these objects before going into the room for the scan. 
 
You will hear “hammering”, clicking, or squealing noises during the scan. You will be given 
earplugs to reduce the noise. You will also be told how to alert the staff if you need them. 
 
In this study, the MRI scan is for research only. But, if we see something that is not normal, you 
will be told and asked to consult your doctor. 
 
As part of the MRI, we will ask you to complete a visual task.  In this task, you will be presented 
with pairs of pictures presented on the left and right side of a screen.  After seeing a pair of 
pictures, and asterisk (*) will appear on either the right or left side of the screen.  You will be 
asked to indicate which side of the screen the asterisk appears by pressing a button, as quickly 
as possible. 
 
 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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After the MRI is complete, the study drug or placebo will be delivered to your home. You will be 
randomly assigned to receive either escitalopram (the study drug) or a placebo.  A placebo is 
not a drug. It looks like the study drug but is not designed to treat any disease or illness. It is 
designed to be compared with a study drug to learn if the study drug has any real effect. Neither 
you, the study staff, nor the study doctor will know if you are receiving the placebo, although this 
can be determined in an emergency. 
 
Study participants will be randomly assigned to either escitalopram or placebo at a 2-to-1 ratio.  
That means, for every two people assigned to escitalopram, 1 will be assigned to placebo.  You 
will have a 67% chance of receiving escitalopram and 33% chance of receiving placebo. 
 
You will initially start on 10mg of study medication.  This is the usual starting dose for 
escitalopram.    
 
Phase 1 Follow-Up Visits: We will schedule a telephone visit 2 weeks later.  We will assess 
your depression symptoms and see if you are having any side effects. You will have a clinic visit 
at weeks 4 and 8 and another telephone visit at week 6. At each contact we will assess your 
depression and any side effects.  You and the study doctor may discuss increasing the dose of 
escitalopram depending on how you tolerate it and how you are doing.  If you are not doing well, 
the telephone visits may be changed to in-person clinic visits or additional visits could be added. 
Additionally, if you are having any side effects, concerns, or feel that your depression is 
worsening, you should contact us at any time to discuss how to proceed. 
 
End of Phase 1/ Phase 2 Baseline Visit (Week 8): During the final Phase 1 visit, your study 
doctor will work with you to determine whether to end study participation or continue to Phase 2:  
 
If your symptoms have significantly improved, your study participation will end.  We will 
discuss continued antidepressant treatment and offer up to two free follow-up visits to 
ease transition back to clinical care. Your study doctor will provide prescriptions during 
this time, but medication will no longer be provided or reimbursed by the study.    
 
If you decide to stop the study at this point for any reason and not proceed to Phase 2, 
we will also offer the two free follow-up visits and discuss other antidepressant treatment 
options with you.  Again, medication will not be provided or reimbursed. 
 
If your symptoms have not significantly improved, or you could not tolerate the study 
drug and had to stop it early, you may continue to Phase 2 of the study. During Phase 2, all 
participants will receive the antidepressant bupropion. There is no placebo involved, so both you 
and the study staff will know what you are taking.  Your study doctor will work with you to stop 
the Phase 1 medication before starting bupropion.   


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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The bupropion dose will start at 150mg in the morning for two weeks.  If tolerated, you will then 
increase the dose to 300mg daily.  This is the dose most people do well on; however, if you do 
not respond well to the medication, your study doctor may discuss increasing it to the maximum 
dose of 450mg daily. 
 
Optional 8 Week MRI Scan: For your Week 8 Visit, you have the option to participate in an 
additional MRI scan. This MRI will be a repeat of the MRI scan that was performed on you 
during your Phase 1 Baseline Visit. This MRI carries no additional risks to you. 
 
 
 
Initial here if you want to participate in this optional 8 week MRI Scan 
 
 
 
Initial here if you do NOT want to participate in this optional 8 week MRI Scan 
 
If you determine that you are uncomfortable with the MRI scan during the Baseline Visit, you 
can always change your mind about taking part in this optional scan. 
 
Phase 2 Follow-Up visits: We will schedule a telephone visit 2 weeks later at week 11.  We will 
assess your depression symptoms and see if you are having any side effects.  You and the 
study doctor will discuss possibly increasing the dose of bupropion depending on how you 
tolerate it and how you are doing.  You will have a clinic visit at weeks 13 and 17 and a 
telephone visit at week 15. At each contact we will assess your depression and any side effects.  
If you are not doing well, the telephone visits may be changed to clinic visits or additional visits 
could be added. Additionally, if you are having any side effects, concerns, or feel that your 
depression is worsening, you should contact us at any time to discuss how to proceed. 
 
End of Phase 2 (Week 17): Two free follow-up visits will be offered to transition to clinical care. 
Medication will no longer be provided or reimbursed. 
 
 
3. Costs to you if you take part in this study: 
 
There is no cost to you for taking part in this study.  If you agree to take part in this research 
study, you and/or your insurance will not have to pay for the tests and treatments that are being 
done only for research.  We will provide study medication to you free of charge. 
 
However, you are still responsible for paying for the usual care you would normally receive for 
the treatment of your illness. This includes treatments and tests you would need even if you 
were not in this study. These costs will be billed to you and/or your insurance.   You have the 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
7 of 14 
right to ask what it may cost you to take part in this study. If you would like assistance, financial 
counseling is available through the Vanderbilt Financial Assistance Program.  The study staff 
can help you contact this program. You have the right to contact your insurance company to 
discuss the costs of your routine care (non-research) further before choosing to be in the study. 
You may choose not to be in this study if your insurance does not pay for your routine care 
(non-research) costs and your doctor will discuss other treatment plans with you. 
 
 
4. Side effects and risks that you can expect if you take part in this study:  
 
Risks of Escitalopram:  Although generally well tolerated, escitalopram does carry the risk of 
side effects.   Common side effects include dry mouth, nausea, diarrhea, constipation; 
dizziness, lifelike dreams; fatigue, tiredness, or difficulty sleeping; appetite change with potential 
weight gain or loss; increased sweating; and loss of interest in sex or difficulty having sex.  
Clinically, most people find these side effects mild and it does not cause them to stop the 
medication.  Rarely, escitalopram may increase the risk of bleeding in your stomach or bowels. 
This risk is high for participants who are taking aspirin, NSAIDs, warfarin, other anticoagulants, 
or have a prior history of bleeding from the stomach or bowels. 
 
Risks of Bupropion: Common side effects include nausea, diarrhea, constipation; dizziness, 
headache, ringing in the ears, tremor / shakiness, lifelike dreams; increased anxiety or agitation; 
difficulty sleeping, decreased appetite and/or weight loss, dry mouth, and increased sweating.  
Bupropion is also associated with the rare risk of seizures, but only in people who have other 
reasons to have seizures. 
 
All antidepressants have the risk of increasing thoughts of suicide. This risk is primarily in 
teenagers and young adults.  It does not appear to be an issue with older adults.  However, as 
people respond differently to medication, you will be monitored for suicidality at each study 
contact.  If you develop any thoughts of wanting to harm yourself, you should contact your study 
doctor immediately. 
 
Risks of stopping antidepressants: Stopping antidepressants too quickly can also result in side 
effects.  This could occur when and if you stop escitalopram or bupropion.  Individuals who 
suddenly stop an antidepressant or cut it down too quickly can develop symptoms of nausea, 
dizziness, tremor, or unusual sensations like tingling in the hands.  Feeling tired and having mild 
muscle aches can also occur.  Finally, you could see irritability, worsening anxiety or worsening 
mood. If you need to stop an antidepressant you are currently taking, or if you wish to stop 
escitalopram or bupropion at the end of your study participation, we will try to avoid these 
problems by slowly reducing the dose of the antidepressant over time.  If you decide to leave 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
8 of 14 
the study early and stop the study medication suddenly, you may also be at risk for these side 
effects. 
 
Risks of Memory Testing: It is not uncommon to experience some stress or frustration during the 
memory testing. However, you may stop the testing at any time if you wish.   
  
Risks of x-ray: As part of this research, you might have x-ray images of parts of your body 
before you have your MRI studies. These x-ray procedures employ radiation and will be used to 
see where a metal object is located in your body. Depending on which part of your body is x- 
rayed, you could receive a dose that is about 3% (0.03 times) the dose a radiation worker is 
allowed to receive in a year or you could receive a lower dose. 
Risks of MRI:  There are no known major risks with an MRI scan.  But, it is possible that harmful 
effects could be found out in the future.  Even though the tunnel is open, it may bother you to be 
placed in a tight space (claustrophobia), and to hear the noise made by the magnet during the 
scan.  You will be given earplugs to reduce the noise.  You may also feel the table vibrate 
and/or move slightly during the scan.  It may be hard to lie on the table during the scan.  If you 
have any metal pieces in your body, they could move during the scan and damage nearby 
tissue or organs. If you have tattoos, these could result in skin injury. 
 
If you use a transdermal patch (medicated patches applied to the skin), you may need to take it 
off during the MRI scan. Transdermal patches slowly deliver medicines through the skin. Some 
patches have metal in the layer of the patch that is not in contact with the skin (the backing). 
You may not be able to see the metal in the backing of these patches. Patches that contain 
metal can overheat during an MRI scan and cause skin burns in the immediate area of the 
patch. Tell the study doctor that you are using a patch and why you are using it (such as, for 
pain, smoking cessation, hormones). Ask your doctor for guidance about removing and 
disposing of the patch before having an MRI scan and replacing it after the procedure. Tell the 
MRI facility that you are using a patch. You should do this when making your appointment and 
during the health history questions you are asked when you arrive for your appointment.  
Loss of Confidentiality:  There is also the potential risk of loss of confidentiality. Every effort will 
be made to keep your information confidential, however, this cannot be guaranteed. 
5.  Payment in case you are injured because of this research study: 
 
If it is determined by Vanderbilt and the Investigator that an injury occurred as a direct result of 
the tests or treatments that are done for research, then you and/or your insurance will not have 
to pay for the cost of immediate medical care provided at Vanderbilt to treat the injury. There are 
no plans for Vanderbilt to pay for the costs of any additional care. There are no plans for 
Vanderbilt to give you money for the injury.  


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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6.  Good effects that might result from this study:  
 
a) The benefits to science and humankind that might result from this study:  We anticipate that 
this study will provide more information about how differences in brain function and brain 
connections influence how people respond to different antidepressant medications.  This may 
lead to better ways of making decisions about what antidepressant medications to use for each 
individual and so benefit others with your condition in the future. 
 
 
b) The benefits you might get from being in this study: By receiving an FDA approved medication 
for treating depression, you may experience an improvement in your condition.   However, as 
people respond differently to medications, personal benefit cannot be guaranteed. 
 
 
7.  Other treatments you could get if you decide not to be in this study: 
   
You do not have to participate in this study to receive treatment for depression.  There are many 
antidepressants, including escitalopram and bupropion, that are commercially available and may 
be prescribed by your physician.  Talk therapy is also available, which is a treatment for 
depression that does not require medications.  If you have questions about these options, your 
study doctor will discuss them with you. 
 
8. Research Results 
 
In the event new information becomes available that may affect the risks and/or benefits 
associated with this study or your willingness to participate in it, you will be notified so you can 
make a decision whether or not to continue your participation in this study. 
 
If results of this study are reported in medical journals or at meetings, you will not be identified 
by name, by recognizable photograph, or by any other means without your specific consent. 
 
 
9.  Payments for your time spent taking part in this study or expenses: 
 
You will be compensated for your participation based on how many visits/assessments you 
attend. 
 
For Phase 1, you will be given: 
 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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Visit 
Amount 
Assessment 
$50.00 
Baseline 
 
• MRI 
$100.00 
• Memory Testing 
$50.00 
Week 4 
$50.00 
Week 8 
$50.00 
Total: 
$300.00 
Optional Week 8 MRI 
$100.00 
Total (including 
optional Week 8 MRI) 
 
$400.00 
 
  
If you end the study at Phase 1 and complete all visits/assessments, you will receive $300.  
If you complete the Optional Week 8 MRI scan, you will receive an additional $100.00. If you are 
unable to complete the study, or miss study visits/assessments, you will only be compensated 
for those visits/tasks completed. 
 
If you continue to Phase 2, you will given: 
 
Visit 
Amount 
Baseline 
$50.00 
Week 13 
$50.00 
Week 17 
$50.00 
Total: 
$150.00 
 
 
If you end the study with both Phases complete, you will receive $450. If you choose to 
complete the optional Week 8 MRI scan, you will receive an additional $100.00. Again, if you 
are unable to complete the study, or miss study visits, you will be compensated only for those 
visits completed. Additionally, during Phase 2, you have the option to receive the study 
medication free of charge through the Vanderbilt pharmacy or through a pharmacy of your 
choice.  We will reimburse you for any out-of-pocket expenses related to your bupropion 
prescription if you choose to use a non-Vanderbilt pharmacy.  You will need to provide us with 
receipts in order to be reimbursed.     
 
We may ask you for your Social Security number and address before you are compensated for 
taking part in this study. 
 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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For individuals that have extreme difficulty with transportation (to where it stops them from 
attending study visits), we have limited funds to assist with transportation.  If this applies to your 
situation, please let the study doctor and the study coordinator know so we can discuss this.  
We do not have funds available to reimburse for gas or mileage. 
 
 
10. Reasons why the study doctor may take you out of this study:   
 
The study doctor may withdraw you from study participation if they determine that, based on the 
initial study interview, you are not eligible to continue in the study. They may also withdraw you 
if you are having difficulty completing study procedures, if you need an immediate referral for 
clinical care, or if he decides it is not in your best interest to continue.  If you are taken out of the 
study, you will be told the reason. 
 
 
 
11. What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should first talk with your study doctor.  We 
may ask you to come in for a final study visit.  Because you will be taking medication, it is 
important to discuss a safe and effective plan for continuing, altering, or stopping the 
medication. If you withdraw or are withdrawn from the study early, you will be compensated for 
the parts of the study you have completed. 
 
 
12. Who to call for any questions or in case you are injured: 
 
If you should have any questions about this research study or if you feel you have been hurt by 
being a part of this study, please feel free to contact the study coordinator Katie Anders, at (615) 
322-1030, or the main study doctor, Dr. Warren Taylor, at (615) 322-1073.  If you cannot reach 
the research staff, you can page the study doctor at (615) 835-0217.  
 
For additional information about giving consent or your rights as a person in this study, to 
discuss problems, concerns, and questions, or to offer input, please feel free to call the 
Vanderbilt University Institutional Review Board Office at (615) 322-2918 or toll free at (866) 
224-8273. 
 
 
13. Clinical Trials Registry.   
 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you.  At most, the website will 
include a summary of the results.  You can search this website at any time. 
 
 
 
14.  Confidentiality:   
 
All reasonable efforts will be made to keep the personal information in your research record 
private and confidential but absolute confidentiality cannot be guaranteed. Your information may 
be shared with institutional and/or governmental authorities, such as the Vanderbilt University 
Institutional Review Board, if you or someone else is in danger or if we are required to do so by 
law. 
 
During the research, if we learn you are having thoughts about suicide or hurting yourself or 
others, the research staff will ask you more questions about your thoughts. Based on your 
response, the staff may provide you with help to get treatment. This may include: 
 
• working with you to contact your doctor, 
• contacting a trusted family member, or a therapist to discuss your thoughts, 
• working with you on a plan that may include getting you to a hospital for safety. 
 
Vanderbilt may share your information, without identifiers, to others or use it for other research 
projects not listed in this form. Vanderbilt, Dr. Warren Taylor and his staff will comply with any 
and all laws regarding the privacy of such information.  There are no plans to pay you for the 
use or transfer of this de-identified information. 
 
This study may have some support from the National Institutes of Health (NIH). If so, your study 
information is protected by a Certificate of Confidentiality.  This Certificate allows us, in some 
cases, to refuse to give out your information even if requested using legal means.  
  
It does not protect information that we have to report by law, such as child abuse or some 
infectious diseases.  The Certificate does not prevent us from disclosing your information if we 
learn of possible harm to yourself or others, or if you need medical help.  
  
Disclosures that you consent to in this document are not protected. This includes putting 
research data in the medical record or sharing research data for this study or future research. 
Disclosures that you make yourself are also not protected. 
 
 


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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15.  Authorization to Use/Disclose Protected Health Information: 
 
All efforts, within reason, will be made to keep your protected health information (PHI) private. 
PHI is your health information that is, or has been, gathered or kept by Vanderbilt as a result of 
your healthcare.  This includes data gathered for research studies that can be traced back to 
you.  Using or sharing (“disclosure”) such data must follow federal privacy rules. By signing the 
consent for this study, you are agreeing (“authorization”) to the uses and likely sharing of your 
PHI.  If you decide to be in this research study, you are also agreeing to let the study team use 
and share your PHI as described below.  
 
As part of the study, Dr. Warren Taylor and his study team may share the results of your study 
and/or non- study linked evaluations, memory testing, and MRI, as well as parts of your medical 
record, to the groups named below. These groups may include Vanderbilt University Institutional 
Review Boards.  Federal privacy rules may not apply to these groups; they have their own rules 
and codes to assure that all efforts, within reason, will be made to keep your PHI private. 
 
The study results will be kept in your research record for at least six years after the study is 
finished.  At that time, the research data that has not been put in your medical record will be 
kept for an unknown length of time.  Any research data that has been put into your medical 
record will be kept for an unknown length of time. 
 
Unless told otherwise, your consent to use or share your PHI does not expire. If you change 
your mind, we ask that you contact Dr. Taylor in writing and let him know that you withdraw your 
consent. His mailing address is 1601 23rd Avenue South, Nashville, TN 37212. At that time, we 
will stop getting any more data about you. But, the health data we stored before you withdrew 
your consent may still be used for reporting and research quality. 
 
 
 
 
If you decide not to take part in this research study, it will not affect your treatment, payment or 
enrollment in any health plans or affect your ability to get benefits. You will get a copy of this 
form after it is signed. 
 
  


Vanderbilt University Institutional Review Board 
Informed Consent Document for Research 
 
Principal Investigator:  Warren D. Taylor, MD                        
Revision Date:    11/07/2019 
Study Title:  Connectivity Affecting the Antidepressant REsponse (The CAARE study) 
Institution/Hospital: Vanderbilt University Medical Center 
 
 
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STATEMENT BY PERSON AGREEING TO BE IN THIS STUDY 
 
I have read this consent form and the research study has been explained to me verbally.  All my 
questions have been answered, and I freely and voluntarily choose to take part in this study.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature of patient/volunteer 
 
 
 
 
 
 
Consent obtained by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name and Title 
 
 
 
 
 
Time