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I
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8806
I
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Vo
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4
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Dec
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20
1
6
:
347
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348
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ce
g
l
u
t
a
m
ate
b
in
d
i
n
g
a
n
d
th
er
ef
o
r
e
d
ec
r
ea
s
e
t
h
e
e
x
cito
t
o
x
icit
y
o
f
n
e
u
r
o
n
s
.
O
n
e
r
an
d
o
m
ized
co
n
tr
o
lled
tr
ial
(
R
C
T
)
o
f
k
eta
m
in
e
w
a
s
co
n
d
u
cted
in
tr
ea
t
m
en
t
-
r
es
is
tan
t
d
ep
r
ess
i
o
n
p
atie
n
ts
,
i
n
clu
d
in
g
p
atien
ts
w
h
o
h
ad
n
o
t
r
esp
o
n
d
ed
to
an
tid
ep
r
ess
a
n
ts
w
it
h
s
a
tis
f
ac
t
o
r
y
th
er
ap
eu
t
ic
r
es
u
lt
s
[
8
]
.
T
r
ea
t
m
en
t
-
r
es
is
ta
n
t
d
ep
r
ess
io
n
r
ef
er
s
to
ca
s
es
o
f
MD
D
th
at
d
o
n
o
t
r
esp
o
n
d
s
ati
s
f
ac
to
r
il
y
to
ap
p
r
o
p
r
iate
co
u
r
s
es
o
f
at
least
t
w
o
a
n
tid
ep
r
ess
a
n
ts
[
9
]
.
P
r
ec
lin
ical
s
tu
d
ie
s
h
a
v
e
in
d
icate
d
t
h
at
r
e
p
ea
ted
d
aily
k
eta
m
in
e
ad
m
i
n
i
s
tr
atio
n
m
a
y
h
a
v
e
n
e
u
r
o
to
x
ic
ef
f
ec
ts
,
p
ar
ticu
lar
l
y
o
n
th
e
f
u
n
ctio
n
o
f
G
A
B
A
er
g
ic
i
n
ter
n
e
u
r
o
n
s
[
8
]
.
T
h
e
ab
u
s
i
v
e
p
o
ten
t
ial
a
n
d
n
e
u
r
o
to
x
icit
y
p
o
s
s
ib
ilit
y
o
f
k
eta
m
in
e
w
ar
r
an
t
t
h
e
s
ea
r
c
h
f
o
r
alter
n
ativ
e
r
ap
id
-
ac
ti
n
g
an
t
id
ep
r
ess
an
ts
.
Sco
p
o
lam
in
e
w
a
s
f
o
u
n
d
to
r
ed
u
c
e
s
y
m
p
to
m
s
o
f
d
ep
r
ess
io
n
w
ith
in
th
r
ee
d
a
y
s
o
f
t
h
e
f
ir
s
t
ad
m
i
n
is
tr
atio
n
[
10
-
12
]
.
T
h
e
Yu
ej
u
p
ill,
an
an
cien
t
C
h
i
n
e
s
e
h
er
b
al
f
o
r
m
u
la
d
esi
g
n
ed
to
tr
ea
t
m
o
o
d
d
is
o
r
d
er
s
,
i
s
s
till
p
o
p
u
lar
to
d
a
y
an
d
f
o
u
n
d
to
b
e
a
r
ap
id
-
o
n
s
et
an
tid
ep
r
ess
a
n
t
w
o
r
k
in
g
t
h
r
o
u
g
h
NM
D
A
r
ec
ep
to
r
s
an
d
B
D
NF
e
x
p
r
ess
io
n
[
13
-
15
]
.
T
h
e
lev
el
o
f
m
ag
n
e
s
iu
m
,
an
o
th
er
N
MD
A
-
r
ec
ep
to
r
an
tag
o
n
is
t,
is
f
o
u
n
d
to
b
e
lo
w
er
th
a
n
n
o
r
m
al
in
T
r
ea
tm
en
t
-
r
es
is
ta
n
t
in
d
iv
id
u
als [
1
6
-
17
].
T
h
ese
f
in
d
i
n
g
s
r
aise
a
n
u
m
b
er
o
f
q
u
esti
o
n
s
.
First,
h
o
w
m
i
g
h
t
d
ep
r
ess
io
n
ca
u
s
e
th
e
atr
o
p
h
y
o
f
n
eu
r
o
n
s
,
an
d
u
n
d
er
w
h
ic
h
s
i
g
n
al
in
g
p
ath
w
a
y
s
,
an
d
n
e
u
r
o
tr
o
p
h
ic
f
ac
to
r
s
?
Seco
n
d
,
h
o
w
m
i
g
h
t
k
eta
m
i
n
e
r
ev
er
s
e
n
e
u
r
o
n
d
a
m
a
g
e
an
d
b
r
ain
m
o
r
p
h
o
lo
g
ica
l
ch
a
n
g
e
s
?
T
h
ir
d
,
h
o
w
m
i
g
h
t
s
co
p
o
la
m
in
e,
th
e
Yu
ej
u
p
ill,
an
d
m
ag
n
e
s
iu
m
,
p
r
o
d
u
ce
a
r
ap
id
a
n
tid
ep
r
ess
a
n
t e
f
f
ec
t s
i
m
ilar
to
th
at
o
f
k
eta
m
i
n
e?
T
o
clar
if
y
th
e
s
e
co
n
ce
r
n
s
,
w
e
r
ev
ie
w
ed
a
lar
g
e
b
o
d
y
o
f
av
ail
ab
le
clin
ical
s
t
u
d
ies
w
it
h
p
atien
t
d
ata
o
n
k
eta
m
in
e
an
tid
ep
r
ess
an
t
e
f
f
e
cts,
s
t
u
d
ies
o
f
m
a
g
n
e
s
i
u
m
a
n
d
s
co
p
o
la
m
i
n
e
alo
n
g
w
it
h
p
r
ec
lin
ical
a
n
i
m
al
ex
p
er
i
m
e
n
ts
o
f
th
e
Y
u
ej
u
p
ill.
W
e
d
is
cu
s
s
r
esear
c
h
th
a
t a
s
s
o
c
iates a
tr
o
p
h
y
o
f
th
e
li
m
b
ic
s
y
s
te
m
a
n
d
th
e
co
r
tex
w
it
h
d
ep
r
ess
io
n
.
W
e
e
x
a
m
in
e
th
e
e
f
f
ec
t o
f
d
ep
r
ess
io
n
in
ter
m
s
o
f
n
e
u
r
o
b
io
lo
g
y
a
n
d
th
e
p
r
o
m
is
i
n
g
n
o
v
el
r
ap
id
an
tid
ep
r
ess
a
n
ts
.
T
h
is
ar
ticle
o
u
tli
n
es
t
h
e
s
t
u
d
y
b
ac
k
g
r
o
u
n
d
,
i
m
p
o
r
tan
t
r
e
s
u
lt
s
,
a
n
d
th
e
li
n
k
ag
e
o
f
t
h
e
u
n
d
er
l
y
in
g
m
ec
h
a
n
i
s
m
s
o
f
r
ap
id
-
ac
ti
n
g
a
n
t
id
ep
r
ess
a
n
ts
.
2.
RE
S
E
ARCH
M
E
T
H
O
D
W
e
u
s
ed
u
n
i
v
er
s
al
s
ta
n
d
ar
d
s
f
o
r
q
u
alitat
iv
e
r
e
s
ea
r
ch
s
tu
d
y
w
h
en
s
elec
ti
n
g
ar
ticle
s
an
d
en
s
u
r
in
g
q
u
alit
y
o
f
th
e
s
t
u
d
ies r
e
v
ie
w
e
d
.
T
h
e
f
o
llo
w
i
n
g
s
ar
e
cr
iter
ia
t
o
in
cl
u
d
e
ar
ticles
in
th
e
s
a
m
p
l
e:
(
a)
p
u
b
lis
h
ed
in
a
p
ee
r
-
r
ev
ie
w
e
d
j
o
u
r
n
al
f
r
o
m
2
0
0
0
to
2
0
1
4
;
(
b
)
cited
in
m
ed
ical
o
r
r
elate
d
liter
atu
r
e;
(
c)
m
a
in
f
o
cu
s
o
n
to
p
ic
o
f
r
ap
id
-
ac
tin
g
an
tid
ep
r
ess
a
n
t
s
.
P
r
o
s
p
ec
ted
ar
ticles
w
er
e
o
b
tain
ed
b
y
ac
ce
s
s
i
n
g
P
u
b
Me
d
d
atab
ase.
Ke
y
w
o
r
d
s
u
s
ed
i
n
cl
u
d
ed
T
r
ea
tm
e
n
t
-
r
es
is
tan
t
d
ep
r
ess
io
n
,
k
eta
m
i
n
e,
NM
D
A
-
r
ec
ep
to
r
,
g
lu
ta
m
a
te
,
Yu
ej
u
p
ill,
an
d
m
ag
n
e
s
iu
m
.
Data
b
ase
s
ea
r
ch
e
s
co
m
b
i
n
ed
y
ield
ed
5
0
ar
ticle
s
f
o
r
p
o
s
s
ib
le
i
n
cl
u
s
io
n
i
n
th
e
s
a
m
p
le.
A
b
s
tr
ac
t
s
o
f
ar
ticles
w
er
e
r
ea
d
to
d
eter
m
i
n
e
w
h
et
h
er
to
o
b
tain
f
u
ll
t
ex
ts
o
f
t
h
e
s
tu
d
ie
s
.
I
f
th
e
ab
s
tr
ac
t
o
f
an
ar
ticle
r
ev
ea
led
th
e
ex
cl
u
s
i
v
e
u
s
e
o
f
s
tan
d
ar
d
ized
d
ata
co
llectio
n
t
o
o
ls
,
an
d
o
th
er
q
u
an
titativ
e
m
ea
s
u
r
es,
th
e
ar
ticle
w
a
s
n
o
t
r
ev
ie
w
ed
f
u
r
th
er
.
A
r
ti
cles
th
a
t
f
o
c
u
s
ed
o
n
r
ap
id
-
ac
ti
n
g
a
n
tid
ep
r
ess
a
n
ts
w
it
h
q
u
alit
ativ
e
m
et
h
o
d
s
w
er
e
ev
alu
a
ted
to
b
e
in
clu
d
ed
in
t
h
e
s
a
m
p
le.
B
ased
o
n
th
e
cr
iter
i
a
f
o
r
in
cl
u
s
io
n
,
t
h
e
r
esear
ch
er
s
s
elec
ted
3
2
ar
ticles
f
o
r
th
e
f
in
a
l
s
a
m
p
le.
T
h
e
f
o
cu
s
o
f
t
h
is
p
ap
er
w
a
s
to
an
al
y
ze
co
llectiv
e
f
in
d
i
n
g
s
o
f
q
u
alita
tiv
e
s
t
u
d
ies
o
n
th
e
b
r
o
ad
t
o
p
ic
o
f
r
ap
id
-
ac
tin
g
a
n
tid
ep
r
ess
an
ts
.
E
ac
h
r
esear
ch
s
tu
d
y
w
a
s
ca
r
ef
u
ll
y
r
ev
ie
w
ed
a
n
d
s
u
m
m
ar
ized
b
y
th
e
r
esear
c
h
er
s
ac
co
r
d
in
g
to
t
h
is
ag
e
n
d
a,
w
h
ic
h
i
n
cl
u
d
ed
th
e
f
o
llo
w
i
n
g
cr
iter
ia:
s
a
m
p
le,
r
esear
ch
d
esi
g
n
,
d
ata
an
al
y
s
is
,
a
n
d
p
r
i
m
ar
y
f
i
n
d
in
g
s
.
3.
RE
SU
L
T
S
A
ND
AN
AL
Y
SI
S
3
.
1
.
E
pid
e
m
io
lo
g
y
o
f
Depre
s
s
io
n
Ma
j
o
r
d
e
p
r
ess
io
n
d
is
o
r
d
er
(
MD
D)
is
o
n
e
o
f
th
e
m
o
s
t
co
m
m
o
n
p
r
ev
alen
t
li
f
eti
m
e
m
e
n
tal
d
is
o
r
d
er
s
in
th
e
Un
ited
States
,
af
f
ec
ti
n
g
ap
p
r
o
x
im
a
tel
y
1
6
.
6
%
o
f
th
e
g
e
n
er
al
p
o
p
u
latio
n
.
A
cc
o
r
d
in
g
t
o
th
e
W
o
r
ld
Hea
lth
Or
g
an
iza
tio
n
(
W
HO;
2
0
1
0
)
,
m
aj
o
r
d
ep
r
ess
io
n
also
ca
r
r
ies th
e
h
ea
v
ie
s
t b
u
r
d
en
o
f
d
is
ab
ilit
y
a
m
o
n
g
m
e
n
tal
a
n
d
b
eh
av
io
r
al
d
is
o
r
d
er
s
.
Ma
j
o
r
d
ep
r
ess
io
n
is
a
m
o
o
d
d
is
o
r
d
er
ch
ar
ac
ter
ized
b
y
a
s
en
s
e
o
f
in
ad
eq
u
ac
y
,
d
esp
o
n
d
en
c
y
,
d
ec
r
ea
s
ed
ac
t
iv
i
t
y
,
p
es
s
i
m
is
m
,
a
n
h
ed
o
n
ia
a
n
d
s
ad
n
es
s
,
w
h
er
e
t
h
ese
s
y
m
p
to
m
s
s
e
v
er
el
y
d
is
r
u
p
t
an
d
ad
v
er
s
el
y
a
f
f
ec
t
t
h
e
p
er
s
o
n
's
li
f
e.
Fu
r
t
h
er
,
d
ep
r
ess
io
n
is
a
li
f
e
-
t
h
r
ea
ten
i
n
g
co
n
d
it
io
n
,
p
r
ev
en
ti
n
g
s
o
m
e
p
atien
ts
f
r
o
m
p
er
f
o
r
m
i
n
g
ac
ti
v
ities
o
f
d
ail
y
liv
in
g
o
r
ca
u
s
i
n
g
s
elf
-
d
estr
u
cti
v
e
b
eh
a
v
io
r
,
ev
en
s
u
i
cid
e
atte
m
p
t
s
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
J
P
HS
I
SS
N:
2252
-
8806
R
a
p
id
-
A
ctin
g
A
n
tid
e
p
r
ess
a
n
ts
a
n
d
Un
d
erlyin
g
Mech
a
n
is
ms (
S
a
mu
el
E
.
W
ils
o
n
)
349
3
.
2
.
N
euro
bio
lo
g
y
o
f
Depre
s
s
io
n
B
r
ain
i
m
a
g
i
n
g
s
t
u
d
ies
o
f
d
e
p
r
ess
iv
e
p
atie
n
ts
r
ev
ea
l
v
o
l
u
m
e
r
ed
u
ctio
n
i
n
li
m
b
ic
b
r
ai
n
r
eg
io
n
s
:
n
o
tab
l
y
i
n
th
e
h
ip
p
o
ca
m
p
u
s
a
n
d
m
P
FC
[
1
-
2
]
.
P
o
s
t
-
m
o
r
te
m
s
tu
d
ie
s
r
ep
o
r
t
a
r
ed
u
ctio
n
o
f
n
eu
r
o
n
s
a
n
d
lo
s
s
o
f
g
lia.
T
h
ese
s
t
u
d
ies
co
n
f
ir
m
a
w
ell
-
es
tab
lis
h
ed
co
n
n
ec
tio
n
b
et
w
ee
n
lo
s
s
o
f
n
e
u
r
o
n
s
a
n
d
d
ep
r
ess
io
n
-
r
elate
d
d
is
o
r
d
er
s
.
Neu
r
o
tr
o
p
h
ic
f
ac
to
r
s
p
la
y
a
m
aj
o
r
r
o
le
in
ce
ll
atr
o
p
h
y
,
an
d
ar
e
s
u
p
p
o
r
ted
b
y
e
v
id
en
ce
t
h
a
t
d
ep
r
ess
io
n
d
ec
r
ea
s
es
ce
r
tain
n
eu
r
o
tr
o
p
h
ic
f
ac
to
r
s
in
l
i
m
b
ic
b
r
ain
r
eg
io
n
s
.
B
DNF
is
o
n
e
o
f
th
e
m
o
s
t
s
tu
d
ie
d
n
eu
r
o
tr
o
p
h
ic
f
ac
to
r
s
.
A
r
ed
u
ct
io
n
o
f
B
DNF
i
n
d
ep
r
ess
ed
s
u
b
j
ec
ts
w
as
r
ev
ea
led
i
n
p
o
s
t
-
m
o
r
tem
s
t
u
d
ies.
T
h
is
w
o
r
k
s
u
g
g
e
s
ted
th
at
B
DNF
i
s
a
s
ig
n
if
ica
n
t
b
io
m
ar
k
er
o
f
d
ep
r
e
s
s
io
n
an
d
tr
ea
t
m
e
n
t
r
esp
o
n
s
e
[
1
8
-
1
9
]
.
On
th
e
o
th
er
h
an
d
,
an
t
id
ep
r
ess
an
t
tr
e
at
m
e
n
t
elev
a
tes
t
h
e
ex
p
r
ess
io
n
o
f
B
D
NF
i
n
th
e
h
ip
p
o
ca
m
p
u
s
an
d
P
FC
[
2
0
]
.
E
v
id
en
ce
a
ls
o
s
h
o
w
s
t
h
at
a
n
tid
ep
r
ess
an
t
tr
ea
t
m
e
n
t
is
co
r
r
elate
d
w
ith
i
n
cr
ea
s
es
in
B
D
NF
i
n
p
o
s
t
-
m
o
r
te
m
b
r
ain
s
o
f
s
u
b
j
ec
ts
o
n
an
tid
ep
r
ess
a
n
ts
at
th
e
ti
m
e
o
f
d
ea
th
.
B
esid
es
B
DNF,
th
er
e
is
ev
id
en
ce
th
at
li
n
k
s
o
th
er
n
eu
r
o
tr
o
p
h
ic/
g
r
o
w
t
h
f
ac
to
r
s
w
it
h
d
ep
r
ess
io
n
,
s
u
c
h
as
v
a
s
c
u
lar
en
d
o
t
h
elial
g
r
o
w
th
f
ac
to
r
(
VE
GF)
,
f
ib
r
o
b
last
g
r
o
w
t
h
f
ac
to
r
2
(
FGF
-
2
)
,
a
n
d
in
s
u
l
in
-
li
k
e
g
r
o
w
t
h
f
ac
to
r
1
(
I
GF
-
1
)
.
W
e
f
u
r
th
er
f
i
n
d
d
ep
r
ess
io
n
an
d
an
tid
ep
r
ess
a
n
t
tr
ea
t
m
e
n
ts
h
a
v
e
co
n
tr
asti
n
g
e
f
f
ec
ts
o
n
t
h
e
ex
p
r
ess
io
n
o
f
th
e
s
e
f
ac
to
r
s
.
T
h
e
“
Ne
u
r
o
tr
o
p
h
ic
h
y
p
o
t
h
esi
s
o
f
d
ep
r
ess
io
n
an
d
an
tid
ep
r
ess
an
t
r
esp
o
n
s
e”
p
r
o
p
o
s
es
th
a
t
d
ep
r
ess
io
n
r
esu
lts
f
r
o
m
d
ec
r
ea
s
ed
n
eu
r
o
tr
o
p
h
ic
s
u
p
p
o
r
t,
w
h
ic
h
c
au
s
e
s
n
e
u
r
o
n
al
atr
o
p
h
y
,
d
ec
r
e
ased
h
ip
p
o
ca
m
p
al
n
eu
r
o
g
en
e
s
is
a
n
d
lo
s
s
o
f
g
lia;
an
tid
ep
r
ess
a
n
t
tr
ea
t
m
e
n
t
r
ev
e
r
s
es
th
i
s
d
ef
ici
t,
an
d
th
er
eb
y
r
ev
er
s
es
t
h
e
b
r
ain
atr
o
p
h
y
a
n
d
n
eu
r
o
n
lo
s
s
[
21
]
.
Neu
r
o
p
last
icit
y
is
f
o
u
n
d
to
p
lay
a
m
aj
o
r
r
o
le
in
m
o
o
d
d
is
o
r
d
er
s
.
Du
r
in
g
d
ep
r
ess
io
n
p
r
o
g
r
ess
io
n
,
n
eu
r
o
g
e
n
e
s
is
,
n
eu
r
o
n
d
e
n
d
r
ites
,
an
d
s
y
n
ap
to
g
e
n
es
is
ar
e
a
lter
ed
b
y
s
tr
ess
a
n
d
an
tid
ep
r
ess
a
n
t
tr
ea
t
m
e
n
t
s
.
I
n
cr
ea
s
in
g
ac
ti
v
it
ies
o
f
n
e
u
r
o
n
s
ca
u
s
e
t
h
e
i
n
s
er
tio
n
o
f
g
lu
ta
m
ate
r
ec
ep
to
r
s
an
d
t
h
e
f
o
r
m
at
io
n
o
f
s
p
in
e
s
y
n
ap
s
es [
22
].
3
.
3
.
Sta
nd
a
rd
Ant
idepre
s
s
a
nts
T
h
e
ty
p
ical
a
n
tid
ep
r
ess
a
n
ts
i
n
clu
d
e
s
elec
ti
v
e
s
er
o
to
n
i
n
r
eu
p
tak
e
i
n
h
ib
ito
r
s
(
SS
R
I
s
)
,
s
er
o
to
n
in
-
n
o
r
ep
in
ep
h
r
in
e
r
eu
p
ta
k
e
i
n
h
ib
ito
r
s
(
SNR
I
s
)
,
s
er
o
to
n
i
n
m
o
d
u
lato
r
s
(
SMs),
tr
ic
y
clic
s
(
T
C
As
)
,
an
d
m
o
n
o
a
m
i
n
e
o
x
id
ase
in
h
ib
ito
r
s
(
M
A
OI
s
)
.
SS
R
I
s
ar
e
t
h
e
n
e
w
er
a
g
en
t
an
d
th
e
m
o
s
t
w
id
el
y
p
r
esc
r
ib
ed
an
d
s
tan
d
ar
d
an
tid
ep
r
ess
a
n
ts
i
n
th
e
tr
ea
t
m
en
t
o
f
MD
D.
T
h
e
r
ea
s
o
n
f
o
r
s
u
ch
a
n
tid
ep
r
ess
an
ts
b
ein
g
t
h
e
f
ir
s
t
-
tr
ial
an
tid
ep
r
e
s
s
a
n
t
tr
ea
t
m
e
n
t
c
h
o
i
ce
h
as
m
ain
l
y
co
m
e
f
r
o
m
t
h
e
m
o
n
o
a
m
in
e
h
y
p
o
th
e
s
is
,
w
h
ic
h
i
s
b
ased
o
n
p
r
ac
tical
ex
p
er
ien
ce
,
a
n
d
i
m
p
r
o
v
ed
to
ler
ab
ilit
y
co
m
p
ar
ed
w
it
h
o
ld
er
a
n
tid
ep
r
ess
a
n
ts
.
H
o
w
e
v
er
,
clo
s
e
to
o
n
e
th
ir
d
o
f
MD
D
p
atien
ts
f
ailed
t
o
r
em
it a
f
ter
u
n
d
er
g
o
i
n
g
s
tan
d
a
r
d
SS
R
I
s
an
t
id
ep
r
ess
an
t tr
ea
t
m
en
t [
6
]
.
3
.
4
.
K
et
a
m
ine
B
ef
o
r
e
co
n
v
e
n
tio
n
a
l
a
n
tid
ep
r
ess
a
n
t
tr
ea
t
m
e
n
t
b
ec
o
m
e
s
e
f
f
ec
tiv
e,
u
s
u
all
y
o
v
er
a
p
er
io
d
o
f
o
n
e
to
t
w
o
m
o
n
t
h
s
,
p
atien
t
s
ca
n
d
is
co
n
ti
n
u
e
t
h
e
m
ed
icatio
n
,
r
esu
l
ti
n
g
i
n
i
n
cr
ea
s
ed
s
u
icid
al
r
is
k
[
23
-
25
]
.
A
s
a
r
es
u
lt,
t
h
e
d
is
co
v
er
y
o
f
tr
ea
t
m
e
n
ts
w
it
h
a
m
o
r
e
r
ap
id
o
n
s
et
ac
tio
n
b
e
ca
m
e
a
m
aj
o
r
g
o
al
o
f
b
io
lo
g
i
ca
l
p
s
y
c
h
iatr
y
.
T
h
e
f
ir
s
t
d
r
u
g
f
o
u
n
d
to
p
r
o
d
u
ce
r
ap
id
im
p
r
o
v
e
m
e
n
t
i
n
m
o
o
d
w
a
s
th
e
NM
D
A
g
lu
ta
m
ate
r
ec
ep
to
r
an
tag
o
n
is
t,
k
eta
m
in
e
t
h
at
d
e
m
o
n
s
tr
ate
s
r
ap
id
an
d
ef
f
ec
ti
v
e
s
y
m
p
to
m
r
elief
i
n
tr
ea
t
m
e
n
t
-
r
esis
tan
t
p
atien
t
s
w
it
h
m
aj
o
r
d
ep
r
ess
io
n
.
R
ec
e
n
t
cli
n
ical
a
n
d
an
i
m
al
s
t
u
d
ies
r
e
v
ea
l
t
h
at
a
s
u
b
an
es
th
etic
d
o
s
e
o
f
k
et
a
m
i
n
e
ca
n
r
ap
id
l
y
allev
iate
d
ep
r
ess
iv
e
s
y
m
p
to
m
s
,
an
d
it
s
e
f
f
ec
t
ca
n
la
s
t
a
f
e
w
d
a
y
s
to
a
w
ee
k
lo
n
g
[
26
]
.
E
x
p
er
i
m
e
n
tal
s
tu
d
ie
s
also
s
u
g
g
est
th
at
th
e
r
ap
id
en
h
an
ce
m
e
n
t
o
f
B
DNF
e
x
p
r
ess
i
o
n
an
d
s
y
n
ap
tic
p
last
ici
t
y
in
g
iv
e
n
b
r
ai
n
r
eg
io
n
s
ar
e
r
esp
o
n
s
ib
le
f
o
r
th
is
e
f
f
ec
t [
2
7
]
.
On
e
s
t
u
d
y
s
u
g
g
est
s
t
h
at
k
eta
m
in
e
-
i
n
d
u
ce
d
a
n
tid
ep
r
ess
an
t
e
f
f
ec
ts
ar
e
a
s
s
o
ci
ated
w
it
h
α
-
a
m
i
n
o
-
3
-
h
y
d
r
o
x
y
-
5
-
m
eth
y
l
-
4
-
is
o
x
az
o
lep
r
o
p
io
n
ic
ac
id
(
A
MP
A
)
r
ec
ep
to
r
s
-
m
ed
iated
u
p
r
eg
u
latio
n
o
f
th
e
m
a
m
m
a
lian
tar
g
e
t
o
f
r
ap
a
m
y
cin
co
m
p
lex
1
(
m
T
OR
C
1
)
an
d
B
DNF
i
n
t
h
e
r
at
h
ip
p
o
ca
m
p
u
s
a
n
d
p
r
ef
r
o
n
ta
l
co
r
tex
[
20
]
.
T
h
e
NM
DA
-
r
ec
ep
to
r
is
p
r
e
-
s
y
n
ap
tic,
w
h
i
le
th
e
A
MP
A
-
r
ec
ep
to
r
is
p
o
s
t
-
s
y
n
a
p
tic.
m
T
OR
C
1
is
a
k
e
y
tr
an
s
cr
ip
tio
n
a
g
e
n
t
t
h
at
a
m
p
li
f
ies
th
e
f
r
eq
u
en
c
y
o
f
e
x
citato
r
y
p
o
s
ts
y
n
ap
tic
cu
r
r
en
t
s
,
an
d
e
x
tr
ac
ell
u
lar
g
lu
ta
m
a
te
i
n
th
e
m
P
F
C
.
A
n
o
t
h
er
r
ep
o
r
t
s
u
g
g
es
ts
t
h
at
k
eta
m
i
n
e
d
ea
ctiv
ate
s
t
h
e
e
u
k
ar
y
o
t
ic
elo
n
g
a
tio
n
f
ac
to
r
2
(
eE
F2
)
k
in
ase,
lead
in
g
to
r
e
d
u
ce
d
eE
F2
p
h
o
s
p
h
o
r
y
latio
n
an
d
th
er
ef
o
r
e
an
in
cr
ea
s
i
n
g
tr
an
s
lat
io
n
o
f
B
DNF.
Fu
r
t
h
er
m
o
r
e,
a
s
in
g
le
d
o
s
e
o
f
k
eta
m
i
n
e
i
n
d
u
ce
d
a
r
ap
id
an
d
co
m
p
lete
r
ev
er
s
al
o
f
s
p
i
n
e
d
ef
icit
an
d
f
u
n
ctio
n
ca
u
s
ed
b
y
t
h
r
ee
w
ee
k
s
o
f
c
h
r
o
n
ic,
u
n
p
r
ed
icta
b
le
s
tr
ess
e
x
p
o
s
u
r
e
[
21
]
.
B
ased
o
n
ca
s
e
s
tu
d
ies,
o
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Keta
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(
E
C
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[
9
]
.
T
h
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e
also
r
ep
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ts
th
at
k
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[
23
-
25
]
.
Ho
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lack
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ter
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Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
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-
8806
I
J
P
HS
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5
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d
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.
3
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6
.
T
he
Yuej
u P
il
l
“
Y
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”
m
ea
n
s
“
escap
in
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n
C
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I
t
w
a
s
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r
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u
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8
0
0
y
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r
s
ag
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b
y
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f
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m
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s
C
h
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Dan
x
i
Z
h
u
.
I
t
is
s
til
l
p
o
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lar
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y
p
r
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to
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ay
to
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d
ep
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n
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lo
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f
ap
p
etite.
Yu
ej
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is
co
m
p
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s
ed
o
f
f
iv
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eq
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al
a
m
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n
t
o
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F
u
,
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Xio
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u
.
An
i
m
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li
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s
h
av
e
s
h
o
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th
a
t
Y
u
ej
u
is
a
n
ef
f
ec
ti
v
e
an
tid
ep
r
ess
an
t
[
13
-
15
]
.
I
t
h
as
b
ee
n
p
r
ev
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s
l
y
r
ep
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ted
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o
l
ex
tr
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f
Yu
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as
a
n
tid
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n
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t
af
ter
a
w
ee
k
-
lo
n
g
ad
m
in
i
s
tr
ati
o
n
[
15
]
.
I
n
ad
d
itio
n
,
o
n
l
y
a
s
i
n
g
le
Y
u
ej
u
eth
a
n
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ex
tr
ac
t a
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m
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to
d
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ate
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ep
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f
f
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L
ea
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ed
Help
les
s
P
ar
ad
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m
.
I
t
s
i
g
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if
ican
t
l
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ed
u
ce
d
t
h
e
n
u
m
b
er
o
f
escap
e
f
ail
u
r
es.
T
h
e
late
n
c
y
to
esca
p
e
also
s
h
o
w
ed
a
tr
en
d
to
d
ec
r
ea
s
e
in
Yu
ej
u
-
tr
ea
ted
m
ic
e
[
13
]
.
Ma
n
y
ac
ti
v
e
co
m
p
o
n
e
n
t
s
i
n
Y
u
ej
u
ar
e
es
s
en
tia
l
o
ils
t
h
at
m
a
y
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e
ex
tr
ac
ted
w
it
h
et
h
a
n
o
l,
s
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c
h
a
s
α
-
c
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e
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n
d
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c
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n
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g
F
u
a
n
d
atr
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li
n
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n
d
h
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n
e
s
o
l
i
n
C
a
n
g
Z
h
u
[
15]
,
[
2
9
]
.
T
h
e
ef
f
ec
ti
v
e
c
o
m
p
o
n
en
t
s
o
f
Y
u
ej
u
r
eg
u
late
g
l
u
ta
m
ate
in
a
w
a
y
s
i
m
ilar
to
k
eta
m
i
n
e,
an
d
r
eq
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ir
e
f
u
r
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er
in
v
est
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at
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.
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ej
u
,
s
i
m
ilar
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k
eta
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i
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e,
r
ap
id
ly
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n
cr
ea
s
ed
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x
p
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B
DNF
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ip
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o
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s
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er
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s
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e
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m
R
N
A
e
x
p
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r
e
m
ain
ed
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n
alter
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[
13
]
.
T
h
is
is
li
k
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y
to
h
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v
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u
lted
f
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r
ap
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s
y
n
th
e
s
i
s
.
B
DNF
p
r
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tein
ex
p
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w
as
r
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n
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d
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2
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o
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r
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2
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w
as
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n
tin
u
o
u
s
l
y
d
ep
h
o
s
p
h
o
r
y
lated
in
k
eta
m
i
n
e
-
tr
ea
ted
m
ice
at
2
4
h
o
u
r
s
[
13
]
.
Yu
ej
u
,
as
an
h
er
b
al
m
ed
ici
n
e,
i
s
f
o
u
n
d
to
b
e
ef
f
ec
tiv
e
an
d
la
s
ti
n
g
as
a
r
ap
id
an
tid
ep
r
ess
an
t
co
m
p
ar
ab
le
to
k
eta
m
i
n
e.
T
h
e
f
ast
i
n
d
u
ct
io
n
o
f
B
DNF
m
a
y
b
e
th
e
u
n
d
er
l
y
in
g
m
ec
h
a
n
is
m
r
esp
o
n
s
ib
le
f
o
r
th
e
r
ap
id
an
tid
ep
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ess
an
t
ac
tio
n
o
f
k
eta
m
in
e
a
n
d
Yu
ej
u
.
T
h
is
d
i
s
co
v
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y
o
p
en
s
a
n
e
w
p
ath
to
s
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k
b
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alter
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m
a
n
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g
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m
e
n
t
f
o
r
MD
D.
Ho
w
e
v
er
,
t
h
e
d
o
s
ag
e
a
m
o
u
n
t
u
s
ed
i
n
(
X
u
e
W
,
e
t a
l,
2
0
1
3
)
is
m
u
c
h
h
i
g
h
er
t
h
an
th
e
r
ec
o
m
m
en
d
ed
p
r
escr
ip
tio
n
u
s
ed
in
d
ep
r
ess
ed
p
atien
t
s
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
J
P
HS
I
SS
N:
2252
-
8806
R
a
p
id
-
A
ctin
g
A
n
tid
e
p
r
ess
a
n
ts
a
n
d
Un
d
erlyin
g
Mech
a
n
is
ms (
S
a
mu
el
E
.
W
ils
o
n
)
351
3
.
7
.
M
a
g
nes
iu
m
Ma
g
n
e
s
i
u
m
Def
ic
ien
c
y
ca
n
s
u
b
j
ec
t
p
atien
ts
to
n
e
u
r
o
p
ath
o
lo
g
y
.
Ma
g
n
e
s
iu
m
io
n
s
r
eg
u
lat
e
ca
lciu
m
io
n
f
lo
w
i
n
ca
lci
u
m
c
h
an
n
el
s
.
C
alci
u
m
a
n
d
g
lu
ta
m
ate
ar
e
b
o
th
e
x
citato
r
y
,
a
n
d
in
e
x
ce
s
s
,
n
eu
r
o
to
x
ic
.
C
alci
u
m
ac
tiv
ate
s
t
h
e
N
MD
A
r
ec
ep
to
r
.
Ma
g
n
esi
u
m
d
ea
cti
v
ates
NM
DA
r
ec
ep
to
r
s
,
o
f
w
h
ic
h
th
e
m
ai
n
f
u
n
ctio
n
s
ar
e
s
y
n
ap
tic
p
last
ici
t
y
co
n
tr
o
l
an
d
m
e
m
o
r
y
f
o
r
m
a
tio
n
.
I
n
m
a
g
n
esi
u
m
d
ef
icie
n
c
y
,
n
e
u
r
o
n
al
d
am
a
g
e
f
r
o
m
o
v
er
l
y
ac
tiv
ated
n
e
u
r
o
n
al
r
ec
ep
to
r
s
co
u
ld
m
an
i
f
e
s
t
as
d
ep
r
ess
io
n
[
16]
,
[
3
0
]
.
T
h
ese
m
a
g
n
esi
u
m
i
o
n
n
eu
r
o
n
a
l
d
ef
icits
m
a
y
b
e
i
n
d
u
ce
d
b
y
s
tr
es
s
h
o
r
m
o
n
e
s
,
d
ietar
y
d
ef
icie
n
cies
o
f
m
ag
n
es
iu
m
as
w
el
l
as
ex
ce
s
s
iv
e
d
ietar
y
ca
lci
u
m
.
R
ef
i
n
ed
f
lo
u
r
co
n
tain
s
o
n
l
y
1
6
%
o
f
th
e
m
ag
n
es
iu
m
f
o
u
n
d
in
w
h
o
le
w
h
ea
t.
E
x
ce
s
s
i
v
e
al
co
h
o
l
d
r
in
k
in
g
ca
n
also
d
ep
lete
m
a
g
n
e
s
i
u
m
s
to
r
a
g
e
i
n
t
h
e
b
o
d
y
.
C
ase
s
t
u
d
ies
s
h
o
w
ed
r
ap
id
r
ec
o
v
er
y
,
l
es
s
th
a
n
7
d
a
y
s
,
f
r
o
m
MD
D
u
s
i
n
g
1
2
5
-
3
0
0
m
g
o
f
m
ag
n
e
s
iu
m
f
o
u
r
ti
m
e
s
a
d
a
y
[
17
]
.
T
h
e
p
o
s
s
ib
ilit
y
t
h
at
m
ag
n
esi
u
m
d
e
f
icie
n
c
y
i
s
th
e
ca
u
s
e
o
f
m
o
s
t
MD
D
is
o
f
en
o
r
m
o
u
s
i
m
p
o
r
ta
n
ce
to
p
u
b
li
c
h
ea
lt
h
,
i
n
t
h
at
it
a
f
f
ec
ts
th
e
p
o
p
u
latio
n
at
lar
g
e,
an
d
is
t
h
er
ef
o
r
e
r
ec
o
m
m
en
d
ed
f
o
r
f
u
r
th
er
an
d
ad
v
a
n
ce
d
r
ese
ar
ch
.
No
n
et
h
eles
s
,
m
a
g
n
e
s
i
u
m
d
ef
icie
n
c
y
o
f
ca
n
b
e
a
m
elio
r
ated
ea
s
il
y
b
y
th
e
co
n
s
u
m
p
tio
n
o
f
w
h
o
le
g
r
ai
n
s
a
n
d
/o
r
n
u
tr
itio
n
a
l
s
u
p
p
lem
en
ts
.
T
h
is
s
i
m
p
le
i
m
p
le
m
en
ta
tio
n
ca
n
p
r
ev
e
n
t
o
r
at
least
lo
w
er
t
h
e
i
n
cid
e
n
ce
o
f
MD
D
a
n
d
t
h
e
u
n
d
esira
b
le
o
u
tco
m
es
ass
o
ciate
d
w
it
h
it.
4.
DIS
CU
SS
I
O
N
C
u
r
r
en
t
co
n
v
e
n
tio
n
al
an
t
id
ep
r
ess
a
n
ts
ac
t
s
lo
w
l
y
,
an
d
it
is
u
r
g
en
t
to
d
ev
elo
p
th
e
t
h
er
ap
eu
ti
cs
th
at
ca
n
q
u
ick
l
y
a
n
d
e
n
d
u
r
i
n
g
l
y
tr
ea
t
d
ep
r
ess
io
n
.
I
n
a
n
e
f
f
o
r
t
to
elu
cid
ate
th
e
m
ec
h
a
n
is
m
s
o
f
r
ap
id
-
ac
ti
n
g
an
tid
ep
r
ess
a
n
ts
i
m
p
licated
in
tr
ea
tin
g
m
aj
o
r
d
ep
r
ess
io
n
d
is
o
r
d
er
,
w
e
co
n
d
u
cted
a
th
o
r
o
u
g
h
liter
at
u
r
e
r
ev
ie
w
o
n
th
e
m
o
s
t r
ec
en
t r
esear
c
h
r
elate
d
to
f
ast
-
o
n
s
et
a
n
tid
ep
r
ess
a
n
ts
a
n
d
th
eir
r
elate
d
m
ec
h
an
is
m
s
.
T
h
e
r
ea
s
o
n
th
a
t
d
ep
r
ess
io
n
ca
u
s
e
s
co
r
tical
atr
o
p
h
y
ca
n
b
e
a
n
s
w
er
ed
b
est
w
it
h
t
h
e
t
h
eo
r
y
k
n
o
w
n
a
s
“
Ne
u
r
o
tr
o
p
h
ic
h
y
p
o
th
e
s
is
o
f
d
ep
r
ess
io
n
”,
w
h
ic
h
s
tates
t
h
at
d
ep
r
ess
io
n
r
esu
lts
f
r
o
m
d
ec
r
ea
s
ed
n
eu
r
o
tr
o
p
h
ic
s
u
p
p
o
r
t,
w
h
ic
h
ca
u
s
es
n
e
u
r
o
n
al
atr
o
p
h
y
,
d
ec
r
ea
s
ed
h
ip
p
o
ca
m
p
a
l
n
eu
r
o
g
en
e
s
is
an
d
lo
s
s
o
f
g
lia.
R
ed
u
ctio
n
o
f
B
DNF
is
also
f
o
u
n
d
i
n
d
ep
r
ess
ed
s
u
b
j
ec
ts
.
Keta
m
i
n
e
r
ev
er
s
e
n
e
u
r
o
n
d
a
m
ag
e
b
y
d
ea
cti
v
ati
n
g
eE
F2
k
in
a
s
e,
an
d
i
n
cr
ea
s
i
n
g
t
h
e
tr
an
s
lat
io
n
o
f
B
DNF,
w
h
ic
h
r
eg
u
lates
n
eu
r
o
n
al
s
u
r
v
i
v
al
a
n
d
d
if
f
e
r
en
tiatio
n
.
C
o
n
s
eq
u
en
tl
y
,
k
eta
m
i
n
e
s
to
p
s
t
h
e
m
o
r
p
h
o
lo
g
ical
c
h
an
g
es o
f
th
e
b
r
ain
d
u
e
to
d
ep
r
ess
io
n
.
T
h
e
p
o
s
s
ib
le
r
ea
s
o
n
th
at
k
eta
m
i
n
e
ac
ts
f
a
s
t
g
lo
b
all
y
i
s
th
a
t
it
w
o
r
k
s
a
g
ain
s
t
g
l
u
ta
m
ate,
th
e
m
ai
n
ex
citato
r
y
n
e
u
r
o
tr
an
s
m
itter
p
r
esen
t
i
n
m
o
r
e
th
a
n
5
0
%
o
f
n
er
v
o
u
s
ti
s
s
u
e.
T
r
ad
itio
n
al
an
tid
ep
r
ess
a
n
ts
ac
t
th
r
o
u
g
h
m
o
n
o
a
m
i
n
es,
s
u
c
h
as
s
er
o
to
n
in
a
n
d
d
o
p
am
in
e,
w
h
ic
h
ar
e
o
n
l
y
p
r
esen
t
in
1
5
%
o
f
n
er
v
o
u
s
t
is
s
u
e.
I
t
i
s
ex
citi
n
g
to
d
is
co
v
er
th
e
m
ec
h
an
is
m
o
f
n
o
v
el
r
ap
id
-
ac
tin
g
a
n
tid
ep
r
ess
a
n
ts
s
u
ch
as
k
eta
m
i
n
e,
s
co
p
o
lam
in
e,
th
e
Yu
ej
u
p
ill,
an
d
m
a
g
n
esi
u
m
an
d
th
eir
r
elatio
n
s
h
ip
w
it
h
g
l
u
ta
m
ate.
I
t
is
u
n
d
er
s
to
o
d
th
at
t
h
e
d
ef
ici
ts
in
d
i
f
f
er
e
n
t
f
o
r
m
s
o
f
n
eu
r
o
p
last
icit
y
,
in
cl
u
d
i
n
g
s
y
n
ap
tic
m
ec
h
an
i
s
m
an
d
n
e
u
r
o
tr
o
p
h
ic
m
ec
h
a
n
i
s
m
,
ar
e
r
esp
o
n
s
ib
le
f
o
r
d
ep
r
ess
io
n
[
1
9
]
,
[
3
1
]
.
B
DNF
is
t
h
e
b
est
s
t
u
d
ied
n
eu
r
o
tr
o
p
h
ic
f
ac
to
r
co
n
ce
r
n
ed
in
d
ep
r
ess
io
n
.
I
n
cr
ea
s
in
g
n
u
m
b
er
s
o
f
s
tu
d
ie
s
s
u
p
p
o
r
t
th
e
v
ie
w
t
h
at
B
DNF
i
s
n
ec
es
s
ar
y
f
o
r
m
ed
i
ati
n
g
an
tid
ep
r
ess
an
t
ef
f
ec
t
s
[
1
8
]
.
T
y
p
ical
m
o
n
o
a
m
i
n
e
an
t
id
ep
r
ess
an
t
s
i
n
cr
ea
s
e
B
DNF
o
n
l
y
af
ter
lo
n
g
-
ter
m
ad
m
i
n
is
tr
atio
n
[
5
]
.
Af
ter
b
ein
g
ca
r
ef
u
ll
y
s
tu
d
ied
an
d
e
x
a
m
in
ed
,
t
h
e
m
ec
h
a
n
i
s
m
s
o
f
th
e
r
ec
en
tl
y
d
is
co
v
er
ed
r
ap
id
-
act
in
g
a
n
tid
ep
r
ess
a
n
ts
,
t
h
e
lin
k
a
g
e
an
d
in
ter
ac
tio
n
s
b
et
w
ee
n
g
l
u
ta
m
ate,
m
T
OR
C
1
s
ig
n
ali
n
g
,
B
DNF,
an
d
s
y
n
ap
to
g
en
es
is
ar
e
t
h
e
k
e
y
to
u
n
d
er
s
tan
d
i
n
g
d
ep
r
ess
io
n
.
F
u
r
th
er
r
esear
ch
f
o
cu
s
ed
o
n
th
ese
ar
ea
s
w
i
ll h
elp
to
d
ev
elo
p
s
af
er
an
d
m
o
r
e
ef
f
ec
ti
v
e
r
ap
id
-
ac
tin
g
a
n
ti
d
ep
r
ess
an
t a
g
e
n
ts
.
T
o
o
u
r
k
n
o
w
led
g
e,
th
is
is
t
h
e
f
ir
s
t
a
n
d
o
n
l
y
s
tu
d
y
th
at
r
e
p
o
r
ts
th
e
co
n
n
ec
tio
n
b
et
w
ee
n
d
if
f
er
e
n
t
r
ap
id
-
ac
tin
g
a
n
tid
ep
r
ess
a
n
ts
a
n
d
t
h
e
m
ec
h
an
i
s
m
s
b
eh
i
n
d
t
h
eir
ac
tio
n
s
.
Dec
r
ea
s
i
n
g
g
lu
t
a
m
ate
tr
an
s
m
i
s
s
io
n
allo
w
s
n
e
u
r
o
n
s
to
r
est
an
d
g
i
v
es
t
h
e
m
t
h
e
o
p
p
o
r
tu
n
it
y
to
r
eg
en
er
ate.
E
n
h
a
n
ci
n
g
B
DN
F
ex
p
r
ess
io
n
in
d
icate
s
u
p
r
eg
u
latio
n
o
f
n
e
u
r
o
p
last
icit
y
,
w
h
ic
h
i
s
f
o
u
n
d
i
n
m
an
y
s
t
u
d
ies
to
allev
iate
d
ep
r
ess
io
n
s
y
m
p
to
m
s
.
Su
f
f
icie
n
t
ev
id
en
ce
s
u
p
p
o
r
ts
th
e
f
u
n
ctio
n
o
f
B
DNF
in
t
h
e
s
u
r
v
iv
a
l
an
d
d
if
f
er
en
tiatio
n
o
f
n
eu
r
o
n
s
.
B
DNF
e
m
p
lo
y
s
ac
u
te
ef
f
ec
ts
o
n
t
h
e
tr
an
s
m
i
s
s
io
n
an
d
p
last
icit
y
o
f
s
y
n
ap
s
e
s
,
an
d
h
eig
h
te
n
s
ex
c
itato
r
y
s
y
n
ap
tic
tr
an
s
m
is
s
io
n
.
Ou
r
r
ec
en
t
s
t
u
d
ies
h
a
v
e
r
ev
ea
led
a
n
o
v
el
co
o
p
er
ativ
e
in
ter
ac
tio
n
b
et
w
ee
n
B
DNF
an
d
g
l
u
ta
m
at
e
in
t
h
e
r
e
g
u
la
tio
n
o
f
d
en
d
r
itic
d
e
v
elo
p
m
e
n
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ate
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CO
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e,
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Y
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4
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Dec
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20
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.
RE
F
E
R
E
NC
E
S
[1
]
C.
S
to
c
k
m
e
ier,
e
t
a
l
.,
“
Ce
ll
u
lar
c
h
a
n
g
e
s
in
th
e
p
o
stm
o
rte
m
h
ip
p
o
c
a
m
p
u
s
in
m
a
jo
r
d
e
p
re
ss
io
n
,
”
Bi
o
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
5
6
(9
)
,
p
p
.
6
4
0
-
6
5
0
,
2
0
0
4
.
[2
]
W
.
Dre
v
e
ts,
e
t
a
l.
,
“
Bra
in
stru
c
tu
r
a
l
a
n
d
f
u
n
c
ti
o
n
a
l
a
b
n
o
rm
a
li
ti
e
s
in
m
o
o
d
d
is
o
rd
e
rs:
im
p
li
c
a
ti
o
n
s
f
o
r
n
e
u
ro
c
ircu
it
ry
m
o
d
e
ls
o
f
d
e
p
re
ss
io
n
,”
Bra
i
n
S
tru
c
t.
Fu
n
c
t
,
v
o
l.
2
1
3
,
p
p
.
93
–
1
1
8
,
2
0
0
8
.
[3
]
G
.
M
a
c
q
u
e
e
n
,
e
t
a
l
.
,
“
P
o
ste
ri
o
r
h
ip
p
o
c
a
m
p
a
l
v
o
lu
m
e
s
a
re
a
ss
o
c
iat
e
d
w
it
h
re
m
is
sio
n
ra
tes
in
p
a
ti
e
n
ts
w
it
h
m
a
jo
r
d
e
p
re
ss
iv
e
d
iso
rd
e
r
,
”
Bi
o
l.
Psy
c
h
i
a
try
,
v
o
l/
issu
e
:
6
4
(
8
)
,
p
p
.
8
8
0
-
8
8
3
,
2
0
0
8
.
[4
]
J.
M
.
Hid
a
lg
o
a
n
d
G
.
Ra
jk
o
w
s
k
a
,
“
M
o
rp
h
o
lo
g
ica
l
b
ra
in
c
h
a
n
g
e
s
in
d
e
p
re
ss
io
n
:
c
a
n
a
n
t
id
e
p
re
ss
a
n
ts
re
v
e
r
se
th
e
m
,”
CNS
Dr
u
g
,
v
o
l.
16
,
p
p
.
361
–
3
7
2
,
2
0
0
2
.
[5
]
R.
Du
m
a
n
a
n
d
L
.
M
.
M
o
n
teg
g
ia,
“
A
n
e
u
ro
tro
p
h
ic
m
o
d
e
l
f
o
r
s
tres
s
-
re
late
d
m
o
o
d
d
iso
r
d
e
rs
,”
Bi
o
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
5
9
(2
)
,
p
p
.
1
1
1
6
–
1
1
2
7
,
2
0
0
6
.
[6
]
M
.
E.
T
h
a
se
,
e
t
a
l
.
,
“
Re
m
issio
n
ra
tes
f
o
ll
o
w
in
g
a
n
ti
d
e
p
re
ss
a
n
t
th
e
ra
p
y
w
it
h
b
u
p
r
o
p
i
o
n
o
r
se
l
e
c
ti
v
e
s
e
ro
to
n
i
n
re
u
p
tak
e
in
h
ib
it
o
rs:
a
m
e
ta
-
a
n
a
l
y
sis
o
f
o
rig
in
a
l
d
a
ta
f
ro
m
7
ra
n
d
o
m
ize
d
c
o
n
tro
ll
e
d
tri
a
ls,
”
J
Cli
n
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
6
6
(8
)
,
p
p
.
9
7
4
-
9
8
1
,
2
0
0
5
.
[7
]
R.
M
.
Be
rm
a
n
,
e
t
a
l
.
,
“
A
n
ti
d
e
p
re
ss
a
n
t
e
ffe
c
ts
o
f
k
e
ta
m
in
e
in
d
e
p
re
ss
e
d
p
a
ti
e
n
ts,
”
Bi
o
l
Psy
c
h
i
a
try
,
v
o
l.
47
,
p
p
.
3
5
1
-
3
5
4
,
2
0
0
0
.
[8
]
C.
A
.
Zara
te,
e
t
a
l
.
,
“
A
ra
n
d
o
m
iz
e
d
tri
a
l
o
f
a
n
N
-
m
e
th
y
l
-
D
-
a
sp
a
rtate
a
n
tag
o
n
ist
i
n
trea
tm
e
n
t
-
re
sista
n
t
d
e
p
re
ss
io
n
,
”
Arc
h
Ge
n
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
6
3
(8
)
,
p
p
.
8
5
6
-
8
6
4
,
2
0
0
6
.
[9
]
A
.
H.
Ro
t,
e
t
a
l.
,
“
Ke
tam
in
e
f
o
r
d
e
p
re
ss
io
n
:
w
h
e
re
d
o
w
e
g
o
f
ro
m
h
e
re
?
”
Bi
o
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
7
2
(7
)
,
p
p
.
5
3
7
-
5
4
7
,
2
0
1
2
.
[1
0
]
D.
Kh
a
jav
i,
e
t
a
l.
,
“
Ora
l
sc
o
p
o
lam
in
e
a
u
g
m
e
n
tatio
n
in
m
o
d
e
ra
te
t
o
se
v
e
re
m
a
jo
r
d
e
p
re
ss
iv
e
d
iso
rd
e
r:
a
ra
n
d
o
m
ize
d
,
d
o
u
b
le
-
b
li
n
d
,
p
lac
e
b
o
-
c
o
n
tro
ll
e
d
stu
d
y
,
”
J
Cli
n
Psy
c
h
ia
try
,
v
o
l/
iss
u
e
:
7
3
(1
1
)
,
p
p
.
1
4
2
8
-
3
3
,
2
0
1
2
.
[1
1
]
B.
Vo
leti,
e
t
a
l
.,
“
S
c
o
p
o
lam
in
e
ra
p
id
ly
in
c
re
a
se
s
m
a
m
m
a
li
a
n
targ
e
t
o
f
ra
p
a
m
y
c
in
c
o
m
p
le
x
1
sig
n
a
li
n
g
,
s
y
n
a
p
to
g
e
n
e
sis,
a
n
d
a
n
ti
d
e
p
re
ss
a
n
t
b
e
h
a
v
io
ra
l
re
sp
o
n
se
s,”
Bi
o
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
7
4
(
1
1
)
,
p
p
.
7
4
2
,
2
0
1
3
.
[1
2
]
L
.
M
.
M
o
n
teg
g
ia
a
n
d
E
.
T
.
Ka
v
a
lali,
“
S
c
o
p
o
lam
in
e
a
n
d
k
e
ta
m
in
e
:
Ev
id
e
n
c
e
o
f
c
o
n
v
e
rg
e
n
c
e
?
”
Bi
o
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
7
4
(
1
1
)
,
p
p
.
7
1
2
,
2
0
1
3
.
[1
3
]
W
.
X
u
e
,
e
t
a
l.
,
“
Yu
e
j
u
p
il
l
ra
p
id
ly
in
d
u
c
e
s
a
n
ti
d
e
p
re
ss
a
n
t
-
li
k
e
e
ffe
c
ts
a
n
d
a
c
tu
a
ll
y
e
n
h
a
n
c
e
s
BDN
F
e
x
p
re
ss
io
n
i
n
m
o
u
se
b
ra
in
,
”
Evid
e
n
c
e
-
b
a
se
d
c
o
mp
lem
e
n
ta
ry
a
n
d
a
lt
e
rn
a
ti
v
e
me
d
ici
ne
,
A
rti
c
le ID
1
8
4
3
6
7
,
p
p
.
9
,
2
0
1
3
.
[1
4
]
X
.
H.
W
e
i,
e
t
a
l.
,
“
A
n
ti
d
e
p
re
ss
a
n
t
e
ff
e
c
t
o
f
Yu
e
ju
-
W
a
n
e
th
a
n
o
l
e
x
trac
t
a
n
d
it
s
f
ra
c
ti
o
n
s
in
m
ice
m
o
d
e
ls
o
f
d
e
sp
a
ir,
”
J
o
u
r
n
a
l
o
f
Et
h
n
o
p
h
a
rm
a
c
o
lo
g
y
,
v
o
l/
issu
e
:
1
1
7
(
2
)
,
p
p
.
339
–
3
4
4
,
2
0
0
8
.
[1
5
]
X
.
H.
W
e
i,
e
t
a
l.
,
“
A
n
ti
d
e
p
re
ss
a
n
t
e
ff
e
c
t
o
f
Yu
e
ju
e
th
a
n
o
l
e
x
trac
t
a
n
d
it
s
c
o
n
stit
u
e
n
ts
in
m
ice
m
o
d
e
ls
o
f
d
e
sp
a
ir,
”
Ch
in
a
P
h
a
rm
a
c
y
,
v
o
l/
issu
e
:
2
0
(3
)
,
p
p
.
1
6
6
–
1
6
8
,
2
0
0
9
.
[1
6
]
G
.
A
.
Eb
y
a
n
d
K.
L
.
Eb
y
,
“
Ra
p
id
re
c
o
v
e
r
y
f
ro
m
m
a
jo
r
d
e
p
re
ss
io
n
u
sin
g
m
a
g
n
e
siu
m
tr
e
a
t
m
e
n
t,
”
M
e
d
Hy
p
o
th
e
se
s
,
v
o
l/
issu
e
:
6
7
(
2
)
,
p
p
.
362
-
7
0
,
2
0
0
6
.
[1
7
]
T
.
S
.
S
.
Ra
o
,
e
t
a
l.
,
“
Un
d
e
rsta
n
d
in
g
n
u
tri
t
io
n
,
d
e
p
re
ss
io
n
a
n
d
m
e
n
tal
il
ln
e
ss
e
s,”
In
d
ia
n
J
Psy
c
h
i
a
try
,
v
o
l/
issu
e
:
5
0
(
2
)
,
p
p
.
77
–
82
,
2
0
0
8
.
[1
8
]
E.
Ca
stre
n
a
n
d
T
.
Ra
n
ta
m
a
k
i,
“
Th
e
ro
le
o
f
BDN
F
a
n
d
it
s
re
c
e
p
to
rs
in
d
e
p
re
ss
io
n
a
n
d
a
n
ti
d
e
p
re
ss
a
n
t
d
ru
g
a
c
ti
o
n
:
re
a
c
ti
v
a
ti
o
n
o
f
d
e
v
e
lo
p
m
e
n
tal
p
las
ti
c
it
y
,”
D
e
v
.
Ne
u
ro
b
io
l
,
v
o
l/
iss
u
e
:
7
0
(
5
)
,
p
p
.
2
8
9
–
2
9
7
,
2
0
1
0
.
[1
9
]
S.
S
e
n
,
e
t
a
l
.
,
“
S
e
ru
m
b
ra
in
-
d
e
riv
e
d
n
e
u
r
o
tro
p
h
ic
f
a
c
to
r,
d
e
p
re
ss
io
n
,
a
n
d
a
n
ti
d
e
p
re
ss
a
n
t
m
e
d
ica
ti
o
n
s
:
m
e
ta
-
a
n
a
l
y
se
s
a
n
d
im
p
li
c
a
ti
o
n
s
,”
Bi
o
l
Psy
c
h
ia
tr
y
,
v
o
l/
issu
e
:
6
4
(5
)
,
p
p
.
5
2
7
–
5
3
2
,
2
0
0
8
.
[2
0
]
W
.
Zh
o
u
,
e
t
a
l.
,
“
Ke
tam
in
e
-
in
d
u
c
e
d
a
n
t
id
e
p
re
ss
a
n
t
e
f
fe
c
ts
a
r
e
a
ss
o
c
iate
d
w
it
h
A
M
P
A
re
c
e
p
to
rs
-
m
e
d
iate
d
u
p
re
g
u
latio
n
o
f
m
T
O
R
a
n
d
BDN
F
in
ra
t
h
ip
p
o
c
a
m
p
u
s
a
n
d
p
re
f
ro
n
tal
c
o
rtex
,
”
Eu
r
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
2
9
(7
)
,
p
p
.
419
-
23
,
2
0
1
4
.
[2
1
]
N.
Li
,
e
t
a
l.
,
“
G
lu
tam
a
te
N
-
m
e
th
y
l
-
d
-
a
sp
a
rtate
r
e
c
e
p
to
r
a
n
tag
o
n
ists
ra
p
id
ly
re
v
e
rse
b
e
h
a
v
io
ra
l
a
n
d
sy
n
a
p
ti
c
d
e
f
icits
c
a
u
se
d
b
y
c
h
ro
n
ic stres
s ex
p
o
su
re
,
”
Bi
o
l.
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
6
9
(
8
)
,
p
p
.
7
5
4
–
7
6
1
,
2
0
1
1
.
[2
2
]
N.
L
i,
e
t
a
l.
,
“
m
T
OR
-
d
e
p
e
n
d
e
n
t
sy
n
a
p
se
f
o
r
m
a
ti
o
n
u
n
d
e
rli
e
s
th
e
ra
p
id
a
n
ti
d
e
p
re
ss
a
n
t
e
ff
e
c
ts
o
f
NMD
A
a
n
tag
o
n
ists,”
S
c
ien
c
e
,
v
o
l
/i
ss
u
e
:
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2
9
(
5
9
9
4
)
,
p
p
.
9
5
9
–
9
6
4
,
2
0
1
0
.
[2
3
]
R.
B.
P
rice
,
e
t
a
l.
,
“
Eff
e
c
ts
o
f
in
trav
e
n
o
u
s
k
e
ta
m
in
e
o
n
e
x
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li
c
it
a
n
d
im
p
li
c
it
m
e
a
su
re
s
o
f
su
icid
a
li
ty
in
trea
t
m
e
n
t
-
re
sista
n
t
d
e
p
re
ss
io
n
,
”
Bi
o
lo
g
ica
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
6
6
(
5
)
,
p
p
.
5
2
2
–
5
2
6
,
2
0
0
9
.
[2
4
]
N.
D
.
G
ra
n
a
d
o
s,
e
t
a
l.
,
“
Ra
p
id
r
e
so
lu
ti
o
n
o
f
su
icid
a
l
id
e
a
ti
o
n
a
f
ter
a
sin
g
le
in
f
u
sio
n
o
f
a
n
N
-
m
e
t
h
y
l
-
D
-
a
sp
a
rtat
e
a
n
tag
o
n
ist
i
n
p
a
ti
e
n
ts
w
it
h
trea
tm
e
n
t
-
re
sista
n
t
m
a
jo
r
d
e
p
re
ss
iv
e
d
is
o
rd
e
r,
”
J
.
Cl
in
.
Psy
c
h
ia
try
,
v
o
l/
is
su
e
:
7
1
(1
2
)
,
p
p
.
1
6
0
5
–
1
6
1
1
,
2
0
1
0
.
[2
5
]
G
.
L
a
r
k
in
a
n
d
A
.
L
.
Be
a
u
trais,
“
A
p
re
li
m
in
a
r
y
n
a
tu
ra
li
stic
stu
d
y
o
f
lo
w
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d
o
se
k
e
ta
m
in
e
f
o
r
d
e
p
re
ss
io
n
a
n
d
su
ici
d
e
id
e
a
ti
o
n
in
t
h
e
e
m
e
r
g
e
n
c
y
d
e
p
a
rtme
n
t,
”
In
ter
n
a
ti
o
n
a
l
J
o
u
rn
a
l
o
f
Ne
u
ro
p
sy
c
h
o
p
h
a
rm
a
c
o
l
o
g
y
,
v
o
l/
i
ss
u
e
:
1
4
(
8
)
,
p
p
.
1
1
2
7
–
1
1
3
1
,
2
0
1
1
.
[2
6
]
R.
M
.
Be
rm
a
n
,
e
t
a
l
.
,
“
A
n
ti
d
e
p
re
ss
a
n
t
e
ffe
c
ts
o
f
k
e
ta
m
in
e
in
d
e
p
re
ss
e
d
p
a
ti
e
n
ts,
”
Bi
o
lo
g
ica
l
Psy
c
h
ia
try
,
v
o
l/
issu
e
:
4
7
(
4
)
,
p
p
.
3
5
1
–
3
5
4
,
2
0
0
0
.
[2
7
]
A
.
E.
A
u
tr
y
,
e
t
a
l
.
,
“
NMDA
re
c
e
p
to
r
b
lo
c
k
a
d
e
a
t
re
st
tri
g
g
e
rs
ra
p
id
b
e
h
a
v
io
ra
l
a
n
ti
d
e
p
re
ss
a
n
t
re
sp
o
n
se
s,”
Na
tu
re
,
v
o
l/
issu
e
:
4
7
5
(
7
3
5
4
)
,
p
p
.
91
–
9
6
,
2
0
1
1
.
Evaluation Warning : The document was created with Spire.PDF for Python.
I
J
P
HS
I
SS
N:
2252
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a
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a
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.
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)
353
[2
8
]
R.
S
.
Du
m
a
n
,
e
t
a
l.
,
“
S
ig
n
a
li
n
g
p
a
th
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a
y
s
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n
d
e
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in
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ra
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re
ss
a
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o
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in
e
,
”
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u
ro
p
h
a
rm
a
c
o
l
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v
o
l/
issu
e
:
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2
(1
)
,
p
p
.
35
-
4
,
2
0
1
2
.
[2
9
]
H.
T
su
n
e
k
i,
e
t
a
l
.
,
“
A
n
ti
a
n
g
io
g
e
n
ic
a
c
ti
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it
y
o
f
β
-
e
u
d
e
s
m
o
l
in
v
it
ro
a
n
d
in
v
iv
o
,
”
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r
o
p
e
a
n
J
o
u
rn
a
l
o
f
Ph
a
rm
a
c
o
lo
g
y
,
v
o
l/
issu
e
:
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1
2
(
2
-
3)
,
p
p
.
1
0
5
–
1
1
5
,
2
0
0
5
.
[3
0
]
D.
V
.
L
o
sif
e
sc
u
,
e
t
a
l.
,
“
Bra
in
b
io
e
n
e
rg
e
ti
c
s
a
n
d
re
sp
o
n
se
to
tr
ii
o
d
o
th
y
ro
n
in
e
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u
g
m
e
n
tatio
n
i
n
m
a
jo
r
d
e
p
re
ss
iv
e
d
iso
rd
e
r,
”
Bi
o
l
Psy
c
h
ia
try
,
v
o
l/
iss
u
e
:
6
3
(1
2
)
,
p
p
.
1
1
2
7
-
3
4
,
2
0
0
8
.
[3
1
]
H.
Ke
ss
e
ls
a
n
d
R.
M
a
li
n
o
w
,
“
S
y
n
a
p
ti
c
A
M
P
A
re
c
e
p
to
r
p
las
ti
c
it
y
a
n
d
b
e
h
a
v
io
r,
”
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u
r
o
n
,
v
o
l/
issu
e
:
6
1
(
1
)
,
p
p
.
3
4
0
–
3
5
0
,
2
0
0
9
.
B
I
O
G
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AUTH
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RS
S
a
m
u
e
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r
a
d
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ted
f
r
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m
M
e
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l
Co
ll
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g
e
o
f
P
e
n
n
sy
lv
a
n
ia
in
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h
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h
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a
n
d
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n
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Re
sid
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y
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o
h
n
s
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o
p
k
in
s
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lt
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a
r
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d
.
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re
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a
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M
e
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c
a
ti
o
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late
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e
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h
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rd
Crit
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p
e
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In
teg
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Ch
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ro
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rsity
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c
h
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e
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in
2
0
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.
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g
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t
h
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m
e
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g
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e
Un
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tate
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n
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sia
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h
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li
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se
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h
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h
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rib
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e
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o
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ti
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ire
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Da
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.
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.
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in
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.
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r
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re
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u
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e
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a
re
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s.
Evaluation Warning : The document was created with Spire.PDF for Python.