Biomedicines,
Год журнала:
2024,
Номер
12(10), С. 2294 - 2294
Опубликована: Окт. 10, 2024
Metabolic
syndrome
(MetS)
is
the
most
common
adverse
drug
reaction
from
psychiatric
pharmacotherapy.
Neuroreceptor
blockade
by
antipsychotic
clozapine
induces
MetS
in
about
30%
of
patients.
Similar
to
insulin
resistance,
impedes
Akt
kinase
activation,
leading
intracellular
glucose
and
glutathione
depletion.
Additional
cystine
shortage
triggers
tryptophan
degradation
kynurenine,
which
a
well-known
AhR
ligand.
Ligand-bound
downregulates
iron
pool,
thereby
increasing
risk
mitochondrial
dysfunction.
Scavenging
stabilizes
transcription
factor
HIF-1,
shifts
metabolism
toward
transient
glycolysis.
Furthermore,
inhibits
AMPK
obesity
liver
steatosis.
Increasing
uptake
activation
prevents
dyslipidemia
damage
and,
therefore,
reduces
MetS.
In
line
with
vitro
results,
feeding
experiments
rats
revealed
disturbed
glucose-/lipid-/iron-metabolism
treatment
hyperglycemia
hepatic
deposits
female
steatosis
anemia
male
animals.
Decreased
energy
expenditure
seems
be
cause
fast
weight
gain
first
weeks
treatment.
patients,
this
due
neuroleptic
correlates
an
improvement
psychotic
syndromes
can
even
used
anticipate
therapeutic
effect
Pharmacological Reviews,
Год журнала:
2024,
Номер
76(6), С. 978 - 1008
Опубликована: Сен. 20, 2024
Both
preclinical
and
clinical
studies
implicate
functional
impairments
of
several
neuroactive
metabolites
the
kynurenine
pathway
(KP),
major
degradative
cascade
essential
amino
acid
tryptophan
in
mammals,
pathophysiology
neurologic
psychiatric
diseases.
A
number
KP
enzymes,
such
as
2,3-dioxygenase
(TDO2),
indoleamine
2,3-dioxygenases
(IDO1
IDO2),
aminotransferases
(KATs),
3-monooxygenase
(KMO),
3-hydroxyanthranilic
oxygenase
(3-HAO),
quinolinic
phosphoribosyltransferase
(QPRT),
control
brain
metabolism
health
disease
are
therefore
increasingly
considered
to
be
promising
targets
for
treatment
disorders
nervous
system.
Understanding
distribution,
cellular
expression,
regulation
enzymes
is
critical
conceptualization
implementation
successful
therapeutic
strategies.
SIGNIFICANCE
STATEMENT:
Studies
have
implicated
Key
regulate
both
disease,
making
them
treating
these
disorders.
Therefore,
understanding
developing
effective
This
review
endeavors
describe
processes
detail.
Progress in Neuro-Psychopharmacology and Biological Psychiatry,
Год журнала:
2024,
Номер
134, С. 111058 - 111058
Опубликована: Июнь 15, 2024
Mounting
evidence
points
towards
a
crucial
role
of
the
kynurenine
pathway
(KP)
in
altered
gut-brain
axis
(GBA)
balance
severe
mental
illness
(SMI,
namely
depression,
bipolar
disorder,
and
schizophrenia)
cardiometabolic
comorbidities.
Preliminary
shows
that
serotonergic
psychedelics
their
analogues
may
hold
therapeutic
potential
addressing
KP
dysregulated
GBA
SMI
In
fact,
aside
from
effects
on
mood,
elicit
improvement
preclinical
models
obesity,
metabolic
syndrome,
vascular
inflammation,
which
are
highly
comorbid
with
SMI.
Here,
we
review
literature
modulation
comorbidities,
application
to
address
brain
systemic
dysfunction
underlying
Psychedelics
might
therapeutically
modulate
comorbidities
either
directly,
via
altering
by
influencing
rate-limiting
enzymes
affecting
levels
available
tryptophan,
or
indirectly,
gut
microbiome,
metabolome,
metabolism,
immune
system.
Despite
promising
preliminary
evidence,
mechanisms
outcomes
remain
largely
unknown
require
further
investigation.
Several
concerns
discussed
surrounding
side
this
approach
specific
cohorts
individuals
Schizophrenia Research Cognition,
Год журнала:
2024,
Номер
38, С. 100328 - 100328
Опубликована: Авг. 29, 2024
Background:
In
the
last
decade,
kynurenine
pathway
(KP)
has
gained
attention
in
pathogenesis
of
cognitive
impairment
schizophrenia
being
at
croassroad
between
neuroinflammation
and
glutamatergic
cholinergic
neurotransmission.However,
clinical
findings
are
scarse
conflicting,
specific
contributions
these
two
systems
to
neurobiology
symptoms
far
from
elucidated.Furthermore,
little
is
known
about
molecular
underpinnings
non-pharmacological
interventions
for
improvement,
including
rehabilitation
strategies.Methods:
The
current
study
examined
72
patients
with
schizophrenia,
divided
clusters
depending
on
severity
impairment,
aim
evaluate
impact
inflammatory
biomarkers
KP
metabolites
functioning.Moreover,
we
studied
their
possible
link
outcome
relation
sessions
remediation
therapy
(CRT)
aerobic
exercise
(AE)
a
longitudinal
arm
42
patients.Results:
Neuroinflammation
appeared
exert
more
pronounced
influence
cognition
exhibiting
higher
functioning,
contrasting
activation
KP,
which
had
greater
individuals
lower
profile.Cognitive
improvements
after
treatments
were
negatively
predicted
by
levels
TNF-α
positively
3-hydroxykynurenine
(3-HK)/kynurenine
(KYN)
ratio,
an
index
kynurenine-3-monooxygenase
(KMO)
enzyme
activity.Conclusion:
Overall,
add
novel
evidence
biological
pointing
differential
role
inducing
deficits
reserve
predicting
outcomes
rehabilitation.
Abstract
The
tryptophan-metabolizing
kynurenine
pathway
(KP)
can
be
activated
by
enhanced
inflammatory
responses
and
has
been
implicated
in
the
pathophysiology
of
schizophrenia.
However,
there
is
little
evidence
for
KP
dysregulation
early
course
psychotic
illness.
We
aimed
to
investigate
potential
immune-mediated
hyperactivity
individuals
with
first-episode
psychosis
(FEP)
relationship
symptom
severity
treatment
response
outcomes.
Serum
immunoassays
were
performed
measure
peripheral
levels
cytokines
(IL-1β,
IL-10,
TNF-a),
rate-limiting
enzymes
(IDO/TDO),
kynurenic
acid
(KYNA)
metabolite
104
antipsychotic-naïve
patients
FEP
80
healthy
controls
(HC).
Positive
Negative
Syndrome
Scale
(PANSS)
Global
Assessment
Functioning
(GAF)
administered
assess
psychopathology
functioning
status
at
admission
following
4-week
antipsychotics.
Cytokine
components
substantially
increased
compared
HC,
before
after
antipsychotic
treatment.
A
significant
positive
correlation
between
pro-inflammatory
IL-1β
KYNA
was
observed
among
patients,
but
not
HC.
Importantly,
within-patient
analysis
revealed
that
those
higher
baseline
experienced
more
severe
negative
symptoms
poorer
clinical
improvement
follow-up.
These
findings
suggest
upregulated
psychosis,
likely
through
induction
IL-1β-dependent
pathways,
raised
might
represent
a
promising
indicator
non-response
medication
FEP.
Frontiers in Psychiatry,
Год журнала:
2025,
Номер
15
Опубликована: Янв. 7, 2025
The
application
of
personalized
medicine
in
patients
with
first-episode
psychosis
(FEP)
requires
tools
for
classifying
according
to
their
response
treatment,
considering
both
treatment
efficacy
and
toxicity.
However,
several
limitations
have
hindered
its
translation
into
clinical
practice.
Here,
we
describe
the
rationale,
aims
methodology
Applied
Pharmacogenetics
Predict
Response
Treatment
First
Psychotic
Episode
(the
FarmaPRED-PEP
project),
which
develop
validate
predictive
algorithms
classify
FEP
antipsychotics,
thereby
allowing
most
appropriate
strategy
be
selected.
These
predictors
will
integrate,
through
machine
learning
techniques,
pharmacogenetic
(measured
as
polygenic
risk
scores)
epigenetic
data
together
clinical,
sociodemographic,
environmental,
neuroanatomical
data.
To
do
this,
project
use
from
two
already
recruited
cohorts:
PEPS
cohort
"Genotype-Phenotype
Interaction
Environment.
Application
a
Predictive
Model
Episodes"
study
PEPs
Spanish
abbreviation)
(N=335)
PAFIP
"Clinical
Program
on
Early
Phases
Psychosis"
(PAFIP
(N
=
350).
cohorts
used
create
predictor,
then
validated
new
cohort,
FarmaPRED
300).
has
been
designed
overcome
identified
studies
psychiatry:
(1)
sample
size;
(2)
phenotype
heterogeneity
definition;
(3)
complexity
(4)
gender
perspective.
global
reach
is
facilitate
effective
deployment
precision
national
health
systems.
Metabolites,
Год журнала:
2025,
Номер
15(3), С. 176 - 176
Опубликована: Март 5, 2025
The
biology
of
schizophrenia
is
highly
complex
and
multifaceted.
Numerous
efforts
have
been
made
over
the
years
to
disentangle
heterogeneity
disease,
gradually
leading
a
more
detailed
understanding
its
underlying
pathogenic
mechanisms.
Two
cardinal
elements
in
pathophysiology
are
neuroinflammation
alterations
neurotransmission.
kynurenine
(KYN)
pathway
(KP)
particular
importance
because
it
inducted
by
systemic
low-grade
inflammation
peripheral
tissues,
producing
metabolites
that
neuroactive
(i.e.,
modulating
glutamatergic
cholinergic
neurotransmission),
neuroprotective,
or
neurotoxic.
Consequently,
KP
at
crossroads
between
two
primary
systems
involved
pathogenesis
schizophrenia.
It
bridges
central
nervous
system
(CNS)
periphery,
as
can
cross
blood–brain
barrier
modulate
neuronal
activity.
Metabolic
syndrome
plays
crucial
role
this
context,
frequently
co-occurs
with
schizophrenia,
contributing
sub-inflammatory
state
able
activate
KP.
This
narrative
review
provides
valuable
insights
into
these
interactions,
offering
framework
for
developing
targeted
therapeutic
interventions
precision
psychiatry
approaches
disorder.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 14, 2024
Summary
Cognitive
deficits
from
dorsolateral
prefrontal
cortex
(dlPFC)
dysfunction
are
common
in
neuroinflammatory
disorders,
including
long-COVID,
schizophrenia
and
Alzheimer’s
disease,
have
been
correlated
with
kynurenine
inflammatory
signaling.
Kynurenine
is
further
metabolized
to
kynurenic
acid
(KYNA)
brain,
where
it
blocks
NMDA
α7-nicotinic
receptors
(nic-α7Rs).
These
essential
for
neurotransmission
dlPFC,
suggesting
that
KYNA
may
cause
higher
cognitive
these
disorders.
The
current
study
found
its
synthetic
enzyme,
KAT
II,
greatly
expanded
expression
primate
dlPFC
both
glia
neurons.
Local
application
of
onto
neurons
markedly
reduced
the
delay-related
firing
needed
working
memory
via
actions
at
nic-α7Rs,
while
inhibition
II
enhanced
neuronal
aged
macaques.
Systemic
administration
agents
reduce
production
similarly
improved
performance
monkeys,
a
therapeutic
avenue
treatment
