Annual Review of Medicine,
Год журнала:
2014,
Номер
66(1), С. 509 - 523
Опубликована: Окт. 23, 2014
Ketamine
is
the
prototype
for
a
new
generation
of
glutamate-based
antidepressants
that
rapidly
alleviate
depression
within
hours
treatment.
Over
past
decade,
there
has
been
replicated
evidence
demonstrating
rapid
and
potent
antidepressant
effects
ketamine
in
treatment-resistant
depression.
Moreover,
preclinical
biomarker
studies
have
begun
to
elucidate
mechanism
underlying
ketamine,
offering
window
into
biology
identifying
plethora
potential
treatment
targets.
This
article
discusses
efficacy,
safety,
tolerability
summarizes
neurobiology
depression,
reviews
mechanisms
prospects
next-generation
rapid-acting
antidepressants.
Psychological Bulletin,
Год журнала:
2014,
Номер
140(3), С. 774 - 815
Опубликована: Янв. 13, 2014
Major
life
stressors,
especially
those
involving
interpersonal
stress
and
social
rejection,
are
among
the
strongest
proximal
risk
factors
for
depression.
In
this
review,
we
propose
a
biologically
plausible,
multilevel
theory
that
describes
neural,
physiologic,
molecular,
genomic
mechanisms
link
experiences
of
social-environmental
with
internal
biological
processes
drive
depression
pathogenesis.
Central
to
signal
transduction
is
hypothesis
threat
adversity
up-regulate
components
immune
system
involved
in
inflammation.
The
key
mediators
response,
called
proinflammatory
cytokines,
can
turn
elicit
profound
changes
behavior,
which
include
initiation
depressive
symptoms
such
as
sad
mood,
anhedonia,
fatigue,
psychomotor
retardation,
social-behavioral
withdrawal.
This
highly
conserved
response
critical
survival
during
times
actual
physical
or
injury.
However,
also
be
activated
by
modern-day
social,
symbolic,
imagined
threats,
leading
an
increasingly
phenotype
may
phenomenon
driving
pathogenesis
recurrence,
well
overlap
several
somatic
conditions
including
asthma,
rheumatoid
arthritis,
chronic
pain,
metabolic
syndrome,
cardiovascular
disease,
obesity,
neurodegeneration.
Insights
from
thus
shed
light
on
important
questions
how
develops,
why
it
frequently
recurs,
strongly
predicted
early
stress,
often
co-occurs
anxiety
certain
disease
conditions.
work
suggest
new
opportunities
preventing
treating
targeting
American Journal of Psychiatry,
Год журнала:
2013,
Номер
170(10), С. 1134 - 1142
Опубликована: Авг. 28, 2013
Intravenous
ketamine
demonstrated
rapid
antidepressant
effects
in
an
optimized
study
design,
improving
depression
severity
64%
of
treatment-resistant
patients
24
hours
after
a
single
dose.
The
double-blind
trial
provides
evidence
for
the
role
N-methyl-d-aspartate
glutamate
receptor
depression,
not
currently
activated
by
existing
drugs.
Cell Reports,
Год журнала:
2018,
Номер
23(11), С. 3170 - 3182
Опубликована: Июнь 1, 2018
Atrophy
of
neurons
in
the
prefrontal
cortex
(PFC)
plays
a
key
role
pathophysiology
depression
and
related
disorders.
The
ability
to
promote
both
structural
functional
plasticity
PFC
has
been
hypothesized
underlie
fast-acting
antidepressant
properties
dissociative
anesthetic
ketamine.
Here,
we
report
that,
like
ketamine,
serotonergic
psychedelics
are
capable
robustly
increasing
neuritogenesis
and/or
spinogenesis
vitro
vivo.
These
changes
neuronal
structure
accompanied
by
increased
synapse
number
function,
as
measured
fluorescence
microscopy
electrophysiology.
induced
appear
result
from
stimulation
TrkB,
mTOR,
5-HT2A
signaling
pathways
could
possibly
explain
clinical
effectiveness
these
compounds.
Our
results
underscore
therapeutic
potential
and,
importantly,
identify
several
lead
scaffolds
for
medicinal
chemistry
efforts
focused
on
developing
plasticity-promoting
compounds
safe,
effective,
treatments
The
neurobiological
mechanisms
underlying
the
induction
and
remission
of
depressive
episodes
over
time
are
not
well
understood.
Through
repeated
longitudinal
imaging
medial
prefrontal
microcircuits
in
living
brain,
we
found
that
spinogenesis
plays
a
critical
role
sustaining
specific
antidepressant
behavioral
effects
maintaining
long-term
remission.
Depression-related
behavior
was
associated
with
targeted,
branch-specific
elimination
postsynaptic
dendritic
spines
on
projection
neurons.
Antidepressant-dose
ketamine
reversed
these
by
selectively
rescuing
eliminated
restoring
coordinated
activity
multicellular
ensembles
predict
motivated
escape
behavior.
Prefrontal
required
for
maintenance
but
their
initial
induction.
Translational Psychiatry,
Год журнала:
2015,
Номер
5(9), С. e632 - e632
Опубликована: Сен. 1, 2015
Although
the
efficacy
of
racemate
ketamine,
a
rapid
onset
and
sustained
antidepressant,
for
patients
with
treatment-resistant
depression
was
serendipitous
finding,
clinical
use
ketamine
is
limited,
due
to
psychotomimetic
side
effects
abuse
liability.
Behavioral
side-effect
evaluation
tests
were
applied
compare
two
stereoisomers
ketamine.
To
elucidate
their
potential
therapeutic
mechanisms,
we
examined
these
on
brain-derived
neurotrophic
factor
(BDNF)-TrkB
signaling,
synaptogenesis
in
selected
brain
regions.
In
social
defeat
stress
learned
helplessness
models
depression,
R-ketamine
showed
greater
potency
longer-lasting
antidepressant
effect
than
S-ketamine
(esketamine).
Furthermore,
induced
more
potent
beneficial
decreased
dendritic
spine
density,
BDNF-TrkB
signaling
prefrontal
cortex
(PFC),
CA3
dentate
gyrus
(DG)
hippocampus
from
depressed
mice
compared
S-ketamine.
However,
neither
stereoisomer
affected
alterations
nucleus
accumbens
mice.
behavioral
effects,
S-ketamine,
but
not
R-ketamine,
precipitated
abnormalities,
such
as
hyperlocomotion,
prepulse
inhibition
deficits
rewarding
effects.
addition,
single
dose
caused
loss
parvalbumin
(PV)-positive
cells
prelimbic
region
medial
PFC
DG.
These
findings
suggest
that,
unlike
can
elicit
effect,
mediated
by
increased
PFC,
DG
CA3.
appears
be
potent,
long-lasting
safe
relative
free
