The role of ceramide in major depressive disorder

Abstract

Major depression is a severe mood disorder with a lifetime prevalence of more than 10%. The pharmacokinetic hypothesis claims that a slow accumulation of antidepressant drugs by acid trapping mainly into lysosomes is responsible for the therapeutic latency and that a lysosomal target mediates the antidepressant effects. The lysosomal lipid metabolizing enzyme acid sphingomyelinase (ASM) cleaves sphingomyelin into ceramide and phosphorylcholine. In a pilot study, the activity of this enzyme was increased in peripheral blood cells of patients with major depressive disorder (MDD), making the ASM an interesting molecular target of antidepressant drugs. Indeed, several antidepressant drugs functionally inhibit ASM. The ASM/ceramide pathway might be a missing link unifying independent findings in neurobiology and the treatment of MDD such as therapeutic latency, oxidative stress, immune activation and increased risk of cardiovascular disease.

Full text

Kopie von subito e.V., geliefert für Psychiatrische Univ.-Klinik (HSL03X03816)
Eur
Arch Psychiatry C!in Neurosci (2009)
259
(Suppl
2):S
J99-S204
DOI
10.I007/s00406-009-0061-x
The
role
of
ceramide in major depressive disorder
Johannes
Kornhuber
· Martin Reichel · Philipp Tripal ·
Teja
W.
Groemer
·Andreas
W.
Henkel·
Christiane
Miihle · Erich Gulbins
©Springer-Verlag
2009
Abstract
Major depression
is
a severe
mood
disorder
with a lifetime prevalence of
more
than
10%.
The
phar-
macokinetic hypothesis claims that a
slow
accumulation
of
antidepressant
drugs
by
acid trapping mainly
into
lyse-
somes is responsible
for
the
therapeutic latency
and
that
a
lysosomal target mediates the antidepressant effects.
The
lysosomal lipid metabolizing enzyme
acid
sphingomyeli-
nase (ASM) cleaves sphingomyelin
into
ceramide
and
phosphory1choline. In a pilot study,
the
activity of
this
enzyme was increased
in
peripheral blood cells
of
patients
with major depressive disorder
(MDD),
making
the
ASM
an
interesting molecular target of antidepressant
drugs.
Indeed, several antidepressant
drugs
functionally inhibit
ASM. The ASM/ceramide pathway might
be
a
missing
link
unifying independent
findings
in
neurobiology
and
the
treatment
of
MDD
such
as
therapeutic latency,
oxidative
stress, immune activation
and
increased risk of
cardiovas-
cular disease.
Keywords Major depressive disorder · Neuroplasticity
hypothesis · Pharmacokinetic hypothesis ·
Acid
sphingomyelinase · Amitriptyline · Fluoxetine ·
Sphingo1ipids · Ceramide · Lysosomes
J.
Kornhuber
(121)
·
M.
Reichel ·
P.
Tripal ·
T.
W.
Groemer
·A.
W.
Henkel·
C.
MUhle
Department
of
Psychiatry
and
Psychotherapy, University of
Erlangen, Schwabachanlage
6,
91054
Erlangen, Germany
e-mail: Johannes.Kornhuber@uk-erlangen.de
E.
Gulbins
Department
of
Molecular Biology, University of Duisburg-
Essen, Essen, Gennany
Major depressive disorder
Major
depressive
disorder
(MDD)
is
a
severe
mood
dis-
order
with
a
lifetime
prevalence
of
more
than
10%
(6].
In
addition
to
the
serious
reduction
in
the
quality
of
life
for
individuals
and
their
families,
major
depression
represents
a
major
risk
factor
for
both
the
development
of
cardio-
vascular
disease,
as
well
as
for
death
after
an
index
myo-
cardial
infarction
l41].
MDD
is
also
a risk
factor
for
osteoporosis
[8]
and
for
the
development
of
reversible
hippocampal
atrophy
[57].
A
broad
variety
of
other
abnormalities
in
MDD
have
been
described:
adrenocortical
activation
[6],
low
serum
cholesterol
[38],
increased
levels
of
parameters
for
oxidative
stress
[13]
and
of
proinftam-
matory
cytokines
including
interleukin-1/J
(IL-I/I)
[24
],
increased
activity
of
serum
phospholipase
A2
[22], a
rela-
tive
or
absolute
increase
in
the
ratio
of
omega
6 to
omega
3
fatty
acids
[44]
and
altered
activities of
protein
kinase
C
[43].
This
has
led
to
the
view
of
MDD
as
an
illness
with
not
only
psychic
manifestations, but
also
with
deleterious
effects
on
many
organ
systems.
Despite
the
devastating
impact of
MDD,
little
is
known
about
its
etiology
and
pathophysiology.
Antidepressant drugs
slowly
accumulate in brain tissue
Acid
trapping
The
pharmacokinetic
hypothesis
assumes
that
slow
intra-
cellular
accumulation
of
antidepressant
drugs
is
related
to
their
therapeutic
latency
[33].
Antidepressant
drugs
usually
share
special
physicochemical
properties,
namely
weak
basicity
and
high
lipophilicity.
These
properties
result
in
extensive tissue
binding,
which
is
evidenced
by
the
high
~Springer

Kopie von subito e.V., geliefert für Psychiatrische Univ.-Klinik (HSL03X03816)
S200
apparent
volume
of distribution of these
drugs
[33,
37].
Lipophilic
weak
bases
accumulate
in
lipid structures
and
within
acidic intracellular compartments
such
as
lyse-
somes.
Their slightly acidic
pH
of 5
is
maintained
by
an
energy-dependent proton
pump.
Weak
bases
cross
the
membranes
in
their neutral
form
by
passive
diffusion.
However,
once
inside
the
lysosome,
they
become
proton-
ated
and
trapped
and
thus cumulate due
to
the
continued
action
of
the
lysosomal proton
pump
(Fig.
1).
This
effect
is
called
"lysosomotl'Opism"
[12]
or
"acid trapping".
Extensive accumulation of antidepressant
drugs
in
acidic
intracellular vesicles
has
been demonstrated
experimen-
tally
[27]
and
is
supported
by
a single-cell simulation
model
[56].
Fluoxetine
as
an
illustrative
example
for
slow
accumulation
in
brain tissue
Fluoxetine
is
a lipophilic
weak
base
with a
logP
value
of
4.5
and
a pKa
value
of 9.62
[4].
Repeated administration of
therapeutic
doses
(20-60 mg/day)
of
fiuoxetine
to
patients
result
in
blood
concentrations of about
0.7
~tM
[5].
In
contrast,
the
absolute plateau concentration
of
fluoxetine
and
its
metabolite norfluoxetine
in
human
brain
tissue
has
been
estimated
to
be
about 10-30
~tM
using
in
vivo
quantification
by
magnetic resonance spectroscopy
[21,
Extracellular fluid
Cytoplasm
Fig.
1
The
figure
shows
a schematic
model
of
how
weak
bases
cumulate intralysosomally, thereby functionally inhibiting
ASM.
A
low
lysosomal
pH
is
maintained
by
an
ATP-driven
proton
pump.
(I)
Weak
bases
(B)
cumulate
in
intracellular
acidic
compartments
because
the
lysosomal membrane
is
much
less permeable
for
the
charged protonated
bases
(BW)
compared
with
the
uncharged
form,
a
phenomenon
called "Iysosomolropism"
or
"acid trapping".
Sub-
stances
with
high log?-
and
high pKa
values
are
highly
concentrated
in
lysosomes.
The
enzyme
ASM
is
attached
by
electrostatic
forces
to
the
inner lysosomal membrane,
and
thereby protected
against
proteolysis.
ASM
is
active
in
the
membrane-hound
form
and
degrades
sphingomyelin
to
phosphorylcholine
and
ceramide.
(2)
High
concen·
trations
of
the
protonated bases disturb
the
binding
of
ASM
to
the
inner
lysosomal
membrane
and
result
in
its
detachment
(3)
and
subsequent inactivation
(4),
possibly involving
pmteolysis
[29].
This
figure
is
taken
from
Kornhuber
et
a!.
[34]
~Springer
Eur
Arch
Psychiatry
Clin
Neurosci
(2009)
259
(Suppl
2):S
199-8204
28].
This
accumulation
in
tissue
is
compatible
with
a
reported
volume
of
distribution
of 12-43
llkg
for
ftuoxetine
in
man
(
1].
Moreover,
concentrations
measured
in
brain
tissue
are
mean
values
over
the
whole
organ,
whereas
values
achieved
in
acidic
compartments
such
as
lysosomes
could
even
be
much
higher.
Most
importantly,
brain
con-
centrations
may
reach
a
plateau
only
after 6-8
months
after
the
initiation
of
treatment
[28].
Other
antidepressants
also
accumulate
slowly
in
human
brain
tissue
Besides
ftuoxetine,
there
is
growing
evidence
for
further
antidepressant
drugs
with
a
similar
accumulation
in
human
brain
tissues
indicated
by
a
high
brain:plasma
ratio
and
a
long
latency
to
plateau
levels.
For
ftuvoxamine,
pharma-
cokinetic
data
were
determined
by
magnetic
resonance
spectroscopy
and
revealed
a
mean
brain:plasma
ratio
of
24:1
at
steady
state
that
was
achieved
after
30
days
of
consistent
daily
dosing.
Information
on
other
antidepres-
sant
drugs
originates
mostly
from
post
mortem
human
brain
tissues
after
rare
cases
of
acute
suicidal
intoxication.
For
example,
the
brain:plasma
ratio
was
found
to
be
6.7:1
for
citalopram
[15]
and
10:1
for
opipramol
[2].
However,
these
values
probably
underestimate
the
true
ratio
because
the
time
period
between
intoxication
and
death
is
usually
to
short
for
the
plateau
levels
in
the
brain
to
be
reached.
Where
experimental
values
are
missing,
the
apparent
volume
of
distribution
of
an
antidepressant
drug
gives
a
hint
about
its
accumulation
in
the
body.
All
three
param-
eters,
pKa,
log
P
and
calculated
lysosomal
concentration
conelate
positively
with
the
apparent
volume
of
distribu-
tion
(Kornhuber
et
al.
unpublished).
Slow
rate
of
accumulation
is
due
to
the
low
close
of
drug
relative
to
its
total
storage
capacity
The
diffusion
of
a
lipophilic
and
weak
basic
molecule
from
the
extracellular
space
to
an
acidic
intracellular
compart-
ment
occurs
within
minutes
to
hours
[56].
Thus,
in
a
cell
culture
system,
drugs
possessing
typical
physicochemical
properties
of
antidepressants
accumulate
within
hours
into
lysosomes
[31,
56].
However,
the
experimental
setting,
where
incubation
of
a
monolayer
of
cells
in
culture
with
a
1,000-fold
volume
of
supernatant
containing
the
test
drug
is
investigated,
does
not
reflect
the
therapeutic
situation
where
milligram
quantities
of
an
antidepressant
drug
are
administered
to
human
patients
with
an
approximate
weight
of
70
kg.
Furthermore,
there
is
no
drug-degrading
metabolic
activity
in
a
neuronal
cell
culture
system,
while
metabolism
and
elimination
lower
the
amount
of
drug
available
in
the
human
body.
The
reason
for
the
long
time
required
to
reach
plateau
tissue
concentrations
in
humans
is

Kopie von subito e.V., geliefert für Psychiatrische Univ.-Klinik (HSL03X03816)
Eur
Arch
Psychiatry
Clin
Neurosci
(2009)
259
(Suppl
2):S
l99-S204
probably the
low
ratio
between
the
amount
of
drug
avail-
able
to
the
total
volume
of
the
storage
compartment.
Slow accumulation
in
lysosomes
may
explain
therapeutic latency
As antidepressant
drugs
slowly
accumulate
in
whole
brain
tissue, it
is
assumed
that
the
accumulation
occurs
similarly
in lysosomes. For
the
initiation
of
antidepressant
effects,
it
may not
be
necessary
to
reach
lysosomal
plateau
concen-
trations
of
the
individual
drug.
Effects
could
already
take
place
at
a certain lysosomal
threshold
concentration.
The
pharmacokinetic hypothesis
assumes
that
the
slow
accu-
mulation of antidepressant
drugs
in
acidic
intracellular
compartments
is
related
to
the
therapeutic
latency
and
further assumes that a lyososomal
target
is
responsible
for
their therapeutic action [33].
Acid sphingomyelinase
(ASM)
as
a molecular target
of
antidepressant drugs
The lipid metabolizing
enzyme
acid
sphingomyelinase
(ASM,
EC
3.1.4.12, sphingomyelin
phosphodiesterase,
optimum
pH
5.0)
is
an
interesting
intra-lysosomal
molec-
ular target
for
antidepressant
drugs.
ASM
is
a
glycoprotein
catalyzing
the
degradation of
sphingomyelin
to
phospho-
rylcholine
and
ceramide.
Ceramide
can
be
further
metab-
olized
to
sphingosine
and
then
to
sphingosine-1-phosphate.
Although
the
biological function of
sphingosine
is
largely
unknown, sphingosine-1-phosphate
has
been
shown
to
be
involved
in
cellular differentiation,
proliferation
and
cell
migration
[52].
Ceramide participates
in
the
induction
of
apoptosis
in
many
cells
activated
by
pro-apoptotic
recep-
tors or stress stimuli
[18].
The
balance
between
ceramide
and sphingosine-1-phosphate
is
referred
to
as
the
"cer-
amide/sphingosine-1-phosphate rheostat"
[11,
55]
and
maintains
an
equilibrium
between
cell
growth
and
death.
ASM is a
key
regulator of
the
cellular
ceramide
level
and
newer studies suggest a potential
role
of
ASM
in
major
depression:
1.
Tri-
and
tetracyclic antidepressant
drugs,
such
as
clomipramine, functionally inhibit
ASM
by
a
mecha-
nism involving their
lysosomal
accumulation,
detach-
ment of
ASM
from
inner
lysosomal
membranes
and
subsequent intralysosomal proteolytic
inactivation
of
ASM
[29]
(Fig.
I).
Antidepressant
dtugs
induce
a
dose-dependent decrease
in
ASM
activity.
However,
even
high
concentrations of
antidepressants
do
not
completely
abolish
ASM
activity.
This
residual
enzy-
matic activity
is
the
reason
why
antidepressant
drugs
S~Ol
do
not
induce
the
clinkal
picturL'
of
NienHmn
···Pi.t:k
disease.
2.
Functional
inhibition
of
ASl\1
is
not
an
t.>xclusivc
property
of
tri-
and
tctrw:yclk
drugs.
hut
i-.
shared
hy
many
antidepressants:
We
have
n!cently
devdnpcd a
structure-propetty
activity
relationship
allllwin!!
the
prediction
of
functional
inhibition
of
ASM
and
chur·
acterized
the
antidepressant
drugs
doxepine,
nuuxe·
tine,
maprotilin,
nortriptyline,
paroxetine
and
sertraline
as
new
functional
ASM
inhibitors
[34}.
Furthermore,
IC
50
values
for
functional
inhibition
of
ASM
are
within
the
therapeutic
range
for
a
number
of
inve~tigated
antidepressant
drugs
(Tripal
et
al.
unpublished
data).
3.
In
a
pilot
study,
we
found
increased
ASM
activity
in
peripheral
blood
mononuclear
cells
in
patients
with
a
major
depressive
episode
[32].
Experiments
in
mice
with
amitriptyline
or
irradiation
show
a
correlation
between
ASM
activity
in
peripheral
organs
and
brain
tissue
(Gulbins
et
al.
unpublishedl.
Taking
both
observations
together,
MDD
might
also
be
associated
with
increased
ASM
activity
in
the
patients'
brain
tissues.
The
mechanism
for
ASM
activation
is
not
fully
understood
at
present,
but
several
factors
ha
vc
been
identified
as
being
involved
in
this
process,
including
oxidative
stress
[47,
581.
nitric
oxide
[58[,
activation
of
protein
kinase
Cti
[59],
alcohol
[45,
491.
and
proin-
tlammatory
stimuli
such
as
TNF-~
[51]
and
IL-l
[23].
Together,
these
data
suggest
ASM
as
a
potential
target
of
antidepressive
drugs.
Ceramide
as
a
missing
link
between
molet·ular
and
clinical abnormalities
in
MDD
Patients
with
MDD
develop
a
wide
range
of
abnormalities
in
organs
such
as
the
hem1
and
bone,
in
blood
chemistry
like
increased
parameters
of
oxidative
stress,
and
increased
levels
of
prointlammatory
cytokines.
These
pathologies
are
not
easily
explained
by
current
depression
hypotheses
such
as
the
monoamine
or
the
neurogenesis
hypothesis.
It
is
more
likely
that
fundamental
cellular
processes
in
central
and
peripheral
cells
are
disturbed
in
MDD.
We
hypothesize
an
altered
activity
of
the
cellular
ASM/ceratnidc
pathway
in
MDD.
The
ASM/ceramide
hypothesis
of
depression
might
explain
several
molecular
and
clinical
aspects
of
MDD.
Oxidative
stress
Acid
sphingomyelinase
plays
a
central
role
~n
immtmit}
and
stress
response
[
18,
20].
Oxidative
stress
mcreases
the
'f)
Springer

Kopie von subito e.V., geliefert für Psychiatrische Univ.-Klinik (HSL03X03816)
S202
activity
of
ASM
[47,
58].
Cytotoxic drugs,
such
as
cisplatin
or
doxorubicin,
ischemia,
ionizing radiation,
or
UV
light,
all
induce
oxidative
stress
which
leads
to
induction of
ASM.
Interestingly, increased oxidative
stress
has
been
reported
in
MDD
[14,
26].
Treatment
with
antidepressants
reduces
indices
of
oxidative
stress,
and
parameters of
oxidative
stress
obviously
normalize
at
the
end of a
depressive
episode
[42].
Enhanced oxidative
stress
in
depressed
patients
may,
thus,
cause
activation
of
the
ASM.
However,
oxidative
stress
itself
may
also
be
the
conse-
quence
of
enhanced
ASM
activity,
as
ceramide
induces
intracellular
reactive
oxygen
species
[ 46]. Oxidative
stress
might
thus
link
this
vicious
circle together
as
both
cause
and
consequence
of
enhanced
activity of
ASM.
Proinflammatory
cytokines
and
adrenocortical
activation
It
is
well
known
that
pro-inflammatory cytokines,
partic-
ularly
IL-
I
fi
contribute
to
the
actions of
stress.
A recent
meta-analysis
found
that
depression
is
positively associated
with
IL-
I
and
IL-6
in
clinical
and
community
samples
with
an
apparent
dose-response relationship between
these
inflammatory
markers
and
depression
[24].
This
associa-
tion
may
be
the
result
of
a complex bidirectional process
in
which
central
nervous
system
correlates of depression alter
immunity
and
vice
versa.
IL-l
f3
is
an
essential mediator
of
the
anti-neurogenic
and
anhedonic
effects
of
stress
[16,
30].
Most
importantly,
it
has
recently
been
shown
that
the
activation
of
ASM
is
necessary
and
sufficient
for
the
formation
of microparticles
from
glial
cells,
an
important
mechanism
for
IL-l p
release
[7].
In
turn,
IL-l results
in
adrenocortical
activation
[
16,
17].
Cardiovascular
disease
A
secretory
form
of
ASM
as
well
as
sphingomyelin
and
ceramide
levels
were
shown
to
be
important participants
in
atherogenesis
[3,
39,
54]
and
might,
thus, contribute
to
the
increased
risk
for
the
development
of cardiovascular
dis-
ease
in
MDD.
Further
metabolic
abnormalities
in
MDD
Other
activities of
the
ASM
and
ceramide
might,
however,
also
contribute
to
MDD.
Ceramide
and,
in
particular,
cer-
amide-1-phosphate
have
been
shown
to
activate
phospho-
lipases
A2
[25,
35].
Ceramide
also
alters
the
fatty
acid
specificity
of
phospholipase
A2
towards
arachidonic
acid
[35].
These
effects
of
ceramide
and
ceramide-1-phosphate
might
result
in
an
increased
activity of
serum
phospholi-
pase
A2
and
an
increased
ratio
of
omega-6
to
omega-3
fatty
acids
which
have
been
observed
in
patients
with
mood
%)
Springer
Eur
Arch
Psychiatry
Clin
Neurosci
(2009)
259
(Suppl
2):S199-S204
disorders
[22,
44].
Ceramide
differentially regulates
pro-
tein
kinase
C
isoforms
inhibiting
protein kinase
C-cx
while
activating
protein
kinase
C-C
[40].
Enhanced activity
of
ASM
may,
therefore,
result
in
an
altered activity of
at
least
some
protein
kinase
C
isoforms
in
major
depression.
Indeed,
decreased
as
well
as
increased
activities
of
protein
kinase
C
have
been
reported
in
depression
[10,
43]
and
it
is
possible
that
the
normalization
of
ceramide
upon
correction
of
an
increased
ASM
activity
also
results
in
a
normaliza-
tion
of
protein
kinase
C
activities.
Sphingomyelinases
and
ceramide
alter
the
function
of transporter
molecules,
including
P-glycoproteins
[53]
and
have
been
shown
to
regulate
ion
channels
[
19,
36,
48].
Of interest
are
the
findings
that
ceramide
reversibly
changes
the
function
of
the
dopamine
transporter
resulting
in
a
decreased
transport
of
dopamine
and
an
increased
transport of serotonin
[50].
By
inhibition of
ASM,
the
therapeutic
action
of
antide-
pressant
drugs
might
result
in
lower
levels of ceramide
and
thus
in
a
reduced
serotonin
transport
via
the
dopamine
transporter.
In
addition
to
a
direct
effect of antidepressant
drugs
on
serotonin
transporters,
this
indirect effect
may
contribute
to
a
delayed
serotonin
reuptake.
Finally,
cera-
mide
has
been
implied
in
vesicular
uptake
[60]
and
an
alteration
of
the
sphingomyelin/ceramide
balance
in
the
cell
membrane
may
change
neurotransmitter uptake
in
the
Psychological
stress
?~
Ox~ative
· \
stress
Antidepressive
.
/r
drugs
____,.
Lysosomal
trapping
---1
A!J
~amide
IL-1/1~
(
Transporte.
r
function
Adrenocortical
Cardiovascular
activation
disease
Fig.
2
Psychological
stress
is
a
major
risk
factor
for
the
development
of
m(\jor
depressive
disorder
and
is
associated
with
oxidative
stress
[26].
In
major
depressive
disorder,
proinflammatory
cytokines
and
peripheral
markers
of
stress
are
increased
[ 14, 26]. Chronic
stressors
such
as
oxidative
stress
or
TNFo:
result
in
the
activation of
acid
sphingomyelinase
(ASNI)
[9,
47,
51,
58],
which
in
turn
leads
to
the
release
of
interleukin-1
(IL-l)
from
brain
astrocytes
[7]. IL-l
activates
the
hypothalamic-pituitary-adrenal
axis
and
elevates
plasma
corti-
costerone
levels
[
17].
Increased
activity
of
ASM
may
be
involved
in
the
development
of
cardiovascular
disease
[3,
39,
54].
The
therapeutic
effect
of
antidepressive
drugs
is
mediated,
at
least
in
part,
by
functional
inhibition
of
ASM
[32].
This
efJect
occurs
with
a
therapeutic
latency
because
of
slow
accumulation
of
antidepressive
drugs
in
acidic
intracellular
vesicles
[33]

Kopie von subito e.V., geliefert für Psychiatrische Univ.-Klinik (HSL03X03816)
Eur Arch Psychiatry
Clin
Neurosci
(2009)
259
(Suppl
2):Sl99-S204
synaptic space, possibly resulting
in
an
imbalance of
neu-
ronal networks
and
the
development of
MDD.
Taken together, the effects of
enhanced
ASM
activity
on
ceramide production
may
have
broad
consequences
for
IL-
1[3
release, adrenocortical activation, synaptic
transmission
and, more specifically, serotonin
uptake
via
the
dopamine
transporter (Fig. 2).
Future work
At
present, it
is
unknown
whether
the
increase
in
ASM
activity is causally linked
to
the
genesis
of
MDD
or
whe-
ther
it
is only a consequence of
the
disease.
Future
studies
should clarify whether or not inhibition of
ASM
is
a
nec-
essary and sufficient precondition of antidepressant
effects
and whether or
not
lysosomal
enzymes
other
than
the
ASM
are inhibited
by
antidepressant
drugs.
The
interplay
between the monoaminergic neurotransmitter
systems
and
the sphingomye!inase-ceramide
pathway
deserves
further
investigation.
Acknowledgments
The
work
was
supported
by
grants
from
DFG
(GU 335/10-3,
KO
947/10-1
).
Conflict of interest statement
JK
has
received
honoraria
or
research support
from
pharmaceutical
companies
(Merz
Pharmaceu-
ticals, GlaxoSmithK!ine,
Bayer
HealthCare,
Novartis)
during
the
last
two years. The other
authors
do
not
declare
any
conflict
of
interest.
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