m.
&Bid Psychklt NeumPsyc~hamaaa4 PrInted In Gnat Britain. All rlghta resewed
lQQ1, Vol.
15. pp. 601-609
0278~6846/91$0.00 0 1991 Pergamon
+ 30 Rru
plc
CONCENTRATION OF CHOLECYSTOKININ IN CEREBROSPINAL FLUID IS DECREASED IN PSYCHOSIS: RELATIONSHIP TO SYMPTOMS AND DRUG RESPONSE MARGERYC. BEINFELDl AND DAVID L.
GARVER2
IDepartment of Pharmacology, University Medical School, St. Louis, MO, U.S.A. and 2Department of Psychiatry and Behavioral Neurobiology University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A. St.
Louis
(Final
form,
March
1991)
Abstract Beinfeld, Margery C. and David L. Garver: Concentration of Cholecystokinin in Cerebrospinal Fluid is Decreased in Psychosis: Relationship to Symptoms and Drug Response. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1991, 15(S): 601-609. Cholecystokinin (CCK) is a neuropeptide which is co-localized and .mesocortical dopamine neurons. CCK resembles an antipsychotlc drug In some pharmacol&cal Levels of CCK In the cerebrospinal fluid (CSF) are reduced schizophrenics In comparison with six controls. Schizophrenic males have lower CSF CCK levels than females. Rapidity of antipsychotic response to haloperldol appeared to drug-free baseline CSF CCK levels.
1. 2. 3. 4. 5.
Keywords : antipsychotic schizophrenia.
response,
cerebrospinal
fluid
within
some mesolimbic
and behavioral tests. in eleven drug-free
to be inversely
cholecystokinin,
related
haloperidol,
Abbreviations: cerebrospinal fluid (CSF), cholecystokinin (CCK), General Clinical Research Center GCRC), Global Assessment Scores (GAS), New Haven Schizophrenic Index (NRSI), Radloimmunoassay (RIA), Schedule for Affective Disorders and Schizophrenia (SADS), Ventral Tegmental Area (VTA).
Introduction Cholecystokinin Its
role
less
(CCK) is
clear.
It
is
modulator
(reviewed
regulation
(Gibbs
co-localized 1980, with
with
Zaborsky each
et
CCK has been
potent
known to display by Beinfeld. et
al
1973)
dopamlne al
the
well
central
CCK is
and
have
while of
thought
opiate
mesolimbic
Many studies
and peripheral
established,
many characteristics 1987).
In the
1985).
is
and to modulate
the
shown to alter
Lane et
Seeman 1984), as
common to
hormone
nervous
role
in
(Far-is
meeocortical
systems.
the brain
a neurotransmitter
to be involved
analgesia
focused
its
is
or neuro-
in appetite et
al
1983).
projections.
on how dopamine
It
(Hokfelt
is et
al
and CCK interact
other.
Wang 1984,
well
a peptide
as a gastrointestinal
al
1986).
dopamine
and to modulate postsynaptlc
excitatory
agents
synthesis
and binding
target
the
activity
cells
in
on dopamine
cell
(Chowdhury
et
(Murphy and Schuster of the
dopaminergic nucleus
activity, 601
1987),
neurons
accumbens. having
al 1982,
in
(Voigt
one of
effects
and
and
the mesencephalon
CCK is
excitatory
release
Dumbrille-Ross
the most on every
as
M. C. Beinfeld and D. L. Garver
602
activity
state
potently
excites
both
of
dopamine
conditions
dopamlne cells
and CCK.
It
Its
et
although
Roberts
et
al
campus and amygdala temporal
cortex
binding
was also
1985).
An earlier
in
depressed Several
CCK levels
the
altered
in
Gerner
to mimic
tests
complex
and nucleus
as under
also
accumbens
by
some
cells
was decreased
negative
as compared
did
It
innervated
in
the
(Crawley
and Wang 1984).
(with
1981)
which
on dopaminergic
immunoreactivity
question
in
not
In the
symptoms)
and decreased
controls.
Decreased
to
and frontal
cortex
any changes
in brain
whether
cerebrospinal
fluid
hlppoin
the
CCK
(Farmery
find
of
schizophrenic
al
patients.
schizophrenic
schizophrenic.‘s
et
the
1985).
by chronic
1985,
Verbanck
patients.
et
Gjerris
CCFCCKlevels.
CSF CCK levels
et
levels
al of
CCK
found
(CSF)
al et
In two other
were
The current
study
CSF CCK is
of
group
of
CSF CCK exist
associated
with
1983)
Implies Jiang
to
have
led
(1984) al
found
(1984)
found
studies
to be elevated
chronically
to
in
determine
role
dopamine
actions
suggestion
in
that
CCK antagonists
inactivation
al
inhibiting
CCK’s
the of
a possible
et
of of
CCK (such
dopamine
as
cells
CCK in the
action
of
1988).
if
schizophrenic
there
patients
is
a difference
as compared
we wanted
in some psychotics,
relative
in
and some of
The ability
depolarization
1985,
was undertaken
in a well-characterized decrements
al
al
substance.
treatment
et
drugs
and Wang 1985)
to prevent
(Bunney
neuroleptic
VanRee et
neuroleptic
drugs
of
(White
antipsychotic
and lorglumide)
neuroleptlc
action
system
(Zetler
be an endogenous
proglumide
if
quite
1987)
hippocampus
In untreated
the mesolimbic
behavioral
caused
al
are
1988)
patients.
CCK’s ability
might
et
1988).
al
patients.
controls
1986,
CCK-like
is
Bunney and Shi
dopamine
(White
schizophrenic
addressed
CCK are
from al
schizophrenic
in
have
of
schizophrenics
(Perry
be decreased
to
no difference
firing
in
dopamine
schizophrenics
of
1981,
(Wang et
and Dunwiddie
that
II
types
study
of
(Tammlnga et
type
all
al
effects
controversial
schizophrenic
studies
concentrations
is
observed
or
Brodie
observed
of
in
with
inhibitory
1987,
et
accumbens
interaction
this
(1983)
(Skirboll
nucleus
the
and Bunney
1984),
the
potentiates
VTA (Freeman al
neurons
in
refractoriness
during
to
in
to
determine
haloperidol
CSF CCK levels
controls.
Secondly,
whether
diminished
treatment.
Methods Subjects Eleven
DSM-III
comparable on the
schizophrenics
age were
adjacent
selected
General
Each gave
Hospital.
the
SADS (Endicott
the
description
six
males
-+ SD),
range 27.7
for
Clinical
consent
to
and Spltzer of
and five
age of
who had recently
clinical females
concurrent Research
studies Center
participate. 1978)
profiles among the
19-44
years.
The controls
2 10.0
years.
The first
been
format using
on the
the
Each underwent for
the
purpose
and six
Psychobiology
(GCRC) at
consisted of
of
University
a structured of
FADS Summary Scores
schizophrenics.
episode
admitted
DSM-III (Endlcott
with
a mean age of
five
males
psychosis
controls
of
Treatment of
interview
and
using
diagnostics. 1978). 27.2
and for There
?: 8.3
and one female
had occurred
Unit
Cincinnati
7 months
were
(mean
with
a mean
to
11 years
CSF CCK. psychosis
?: 3.4 years)
(5.2
prior
(except
for
an 8:00
AM lumbar
Study
lorazepam
Following
least
In the for
schizophrenics.
behavioral
recovery
of
Each had been
control)
for
at
least
drug
free
14 days
prior
to
CSF.
responders.
”
trial
responded
achieve
of
to
were
to
to
free
respond
haloperidol
the modified
at baseline
response”
(number
baseline
of
more fully
days
showed
a 55% improvement
having
an “early
failed
to
responded
Assessment
discontinued
the
haloperidol
periods
times
weekly
treatment for
CCK levels.
(1988).
scores
to haloperidol.” response
time
of
until
of
the
et
In less
than
to achieve
more than
28 days
from
the
the
of
so as to
1984)
were
The “latency 55% reduction
with could
are
and who
be described
schizophrenics
facility;
for
described
haloperidol
haloperidol
as
either
treatment
such
of of
schizophrenic protocol
18 days of
who had
scores
al
response.
treated
The remainder
a
dose-adjusted
(Zemlan of
“lithium
Patients
Paychoels
clinical
patients
transfer/discharge to
rate
the
be discharged
and began
haloperidol-treated
Details
Schizophrenic
from baseline
(NBSI)
necessary
each
were
levels
during
considered
dose.
35 days.
determine
lithium
lithium
trial
up to
treatment
therapeutic
who could
were
In divided
Index
to
to
patients
symptoms
by day 14 of
or non-responders
withdrawn
with
the
from
hospitalized
in
collection
were
assayed
the
“late
Only
at
or had
schizophrenfds
are
haloperidol.”
Instruments
was
samples
al
response
at
as
alone.
15 mg/day
for
alone
response
psychotic
alone
a standardized
lithium
at
was determined
show comparable
described
lithium
haloperidol
CSF
et
to
plasma
of
baseline
in Garver
on lithium positive
of
substantial
New Raven Schizophrenic
scores)
with
showed
of
received
a trial
beginning
and three
psychosis
comparisons
in (RIA)
reacts
with
indication
the
tubes
kept
the
assay
those
continued
patients
with
patients
haloperidol
assessed
the
If
9 It 2 ng haloperldol/ml
according
CSF
beginning
virtually
who failed
therapeutic
schizophrenic
1988)
days.
they
alone,
Patients
al
twelve
two week trial,
of
for
studies,
et
on lithium
not
study
intermittently
puncture
baseline (Garver
at
not
the
603
response
Design
protocol for
to
and antipsychotic
lateral
Immediately and patients
at
until
-7O’C
laboratory et
1981)
CCK-33 and CCK-8, of
bimodal
from
closer
to
the the
were
shipped
at M Beinfeld al
but
distribution patients
position
immersed
controls
(Beinfeld
data
decubitus
fails of
in dry
St.
ice
detect
CSF CCK in
was performed
to
in one ml aliquots,
at bedside.
In an identical
for
Louis
7 & 8 of to
ice-methanol
performed
on dry at
on mls
at L4 or L5 level
assay.
Immunoreactive
University
the
using
CSF tap.
unsulfated the
CCK-8.
patients
a CCK radioimmuno-
Though
fully there
patients, with
The CSF CCK was
The antibody
schizophrenic
contrast
Collections
manner.
lowest
crosawas no
a median CCK
split
values
controls.
Data Analysis Significance statistic Spearman
for rank
of
differences
independent method
(rs).
between samples.
subject Significance
groups of
was evaluated correlations
with were
the Mann-Whitney
assessed
with
the
vs.
604
M.C.BeinfeldandD.L.Garver
Results CSF CCK in Schizophrenicsand Controls Mean drug-free CSF CCK levels were 15.5 ? 4.5 pmol/ml (range 6.9 - 23.4 pmol/ml) In the schizophrenics and 27.4 ? 5.1 pmol/ml (range 19.8 - 33.0 pmol/ml) in the controls (MannWhitney a'= 3.02; p < 0.002). as shown in Fig 1.
Interestingly,male schizophrenicshad
lower CSF CCK levels than females, 12.7 + 3.4 pmol/ml vs. 18.9 f 3.05 pmol/ml (MannWhitney z - 2.37; p < 0.01). The single female control had a CSF CCK value (29.4) similar to that of control males (27.0 ?:5.7 pmol/ml).
26 0
0
p
&Bid Psychklt NeumPsyc~hamaaa4 PrInted In Gnat Britain. All rlghta resewed
lQQ1, Vol.
15. pp. 601-609
0278~6846/91$0.00 0 1991 Pergamon
+ 30 Rru
plc
CONCENTRATION OF CHOLECYSTOKININ IN CEREBROSPINAL FLUID IS DECREASED IN PSYCHOSIS: RELATIONSHIP TO SYMPTOMS AND DRUG RESPONSE MARGERYC. BEINFELDl AND DAVID L.
GARVER2
IDepartment of Pharmacology, University Medical School, St. Louis, MO, U.S.A. and 2Department of Psychiatry and Behavioral Neurobiology University of Alabama at Birmingham, Birmingham, AL 35294, U.S.A. St.
Louis
(Final
form,
March
1991)
Abstract Beinfeld, Margery C. and David L. Garver: Concentration of Cholecystokinin in Cerebrospinal Fluid is Decreased in Psychosis: Relationship to Symptoms and Drug Response. Prog. NeuroPsychopharmacol. & Biol. Psychiat. 1991, 15(S): 601-609. Cholecystokinin (CCK) is a neuropeptide which is co-localized and .mesocortical dopamine neurons. CCK resembles an antipsychotlc drug In some pharmacol&cal Levels of CCK In the cerebrospinal fluid (CSF) are reduced schizophrenics In comparison with six controls. Schizophrenic males have lower CSF CCK levels than females. Rapidity of antipsychotic response to haloperldol appeared to drug-free baseline CSF CCK levels.
1. 2. 3. 4. 5.
Keywords : antipsychotic schizophrenia.
response,
cerebrospinal
fluid
within
some mesolimbic
and behavioral tests. in eleven drug-free
to be inversely
cholecystokinin,
related
haloperidol,
Abbreviations: cerebrospinal fluid (CSF), cholecystokinin (CCK), General Clinical Research Center GCRC), Global Assessment Scores (GAS), New Haven Schizophrenic Index (NRSI), Radloimmunoassay (RIA), Schedule for Affective Disorders and Schizophrenia (SADS), Ventral Tegmental Area (VTA).
Introduction Cholecystokinin Its
role
less
(CCK) is
clear.
It
is
modulator
(reviewed
regulation
(Gibbs
co-localized 1980, with
with
Zaborsky each
et
CCK has been
potent
known to display by Beinfeld. et
al
1973)
dopamlne al
the
well
central
CCK is
and
have
while of
thought
opiate
mesolimbic
Many studies
and peripheral
established,
many characteristics 1987).
In the
1985).
is
and to modulate
the
shown to alter
Lane et
Seeman 1984), as
common to
hormone
nervous
role
in
(Far-is
meeocortical
systems.
the brain
a neurotransmitter
to be involved
analgesia
focused
its
is
or neuro-
in appetite et
al
1983).
projections.
on how dopamine
It
(Hokfelt
is et
al
and CCK interact
other.
Wang 1984,
well
a peptide
as a gastrointestinal
al
1986).
dopamine
and to modulate postsynaptlc
excitatory
agents
synthesis
and binding
target
the
activity
cells
in
on dopamine
cell
(Chowdhury
et
(Murphy and Schuster of the
dopaminergic nucleus
activity, 601
1987),
neurons
accumbens. having
al 1982,
in
(Voigt
one of
effects
and
and
the mesencephalon
CCK is
excitatory
release
Dumbrille-Ross
the most on every
as
M. C. Beinfeld and D. L. Garver
602
activity
state
potently
excites
both
of
dopamine
conditions
dopamlne cells
and CCK.
It
Its
et
although
Roberts
et
al
campus and amygdala temporal
cortex
binding
was also
1985).
An earlier
in
depressed Several
CCK levels
the
altered
in
Gerner
to mimic
tests
complex
and nucleus
as under
also
accumbens
by
some
cells
was decreased
negative
as compared
did
It
innervated
in
the
(Crawley
and Wang 1984).
(with
1981)
which
on dopaminergic
immunoreactivity
question
in
not
In the
symptoms)
and decreased
controls.
Decreased
to
and frontal
cortex
any changes
in brain
whether
cerebrospinal
fluid
hlppoin
the
CCK
(Farmery
find
of
schizophrenic
al
patients.
schizophrenic
schizophrenic.‘s
et
the
1985).
by chronic
1985,
Verbanck
patients.
et
Gjerris
CCFCCKlevels.
CSF CCK levels
et
levels
al of
CCK
found
(CSF)
al et
In two other
were
The current
study
CSF CCK is
of
group
of
CSF CCK exist
associated
with
1983)
Implies Jiang
to
have
led
(1984) al
found
(1984)
found
studies
to be elevated
chronically
to
in
determine
role
dopamine
actions
suggestion
in
that
CCK antagonists
inactivation
al
inhibiting
CCK’s
the of
a possible
et
of of
CCK (such
dopamine
as
cells
CCK in the
action
of
1988).
if
schizophrenic
there
patients
is
a difference
as compared
we wanted
in some psychotics,
relative
in
and some of
The ability
depolarization
1985,
was undertaken
in a well-characterized decrements
al
al
substance.
treatment
et
drugs
and Wang 1985)
to prevent
(Bunney
neuroleptic
VanRee et
neuroleptic
drugs
of
(White
antipsychotic
and lorglumide)
neuroleptlc
action
system
(Zetler
be an endogenous
proglumide
if
quite
1987)
hippocampus
In untreated
the mesolimbic
behavioral
caused
al
are
1988)
patients.
CCK’s ability
might
et
1988).
al
patients.
controls
1986,
CCK-like
is
Bunney and Shi
dopamine
(White
schizophrenic
addressed
CCK are
from al
schizophrenic
in
have
of
schizophrenics
(Perry
be decreased
to
no difference
firing
in
dopamine
schizophrenics
of
1981,
(Wang et
and Dunwiddie
that
II
types
study
of
(Tammlnga et
type
all
al
effects
controversial
schizophrenic
studies
concentrations
is
observed
or
Brodie
observed
of
in
with
inhibitory
1987,
et
accumbens
interaction
this
(1983)
(Skirboll
nucleus
the
and Bunney
1984),
the
potentiates
VTA (Freeman al
neurons
in
refractoriness
during
to
in
to
determine
haloperidol
CSF CCK levels
controls.
Secondly,
whether
diminished
treatment.
Methods Subjects Eleven
DSM-III
comparable on the
schizophrenics
age were
adjacent
selected
General
Each gave
Hospital.
the
SADS (Endicott
the
description
six
males
-+ SD),
range 27.7
for
Clinical
consent
to
and Spltzer of
and five
age of
who had recently
clinical females
concurrent Research
studies Center
participate. 1978)
profiles among the
19-44
years.
The controls
2 10.0
years.
The first
been
format using
on the
the
Each underwent for
the
purpose
and six
Psychobiology
(GCRC) at
consisted of
of
University
a structured of
FADS Summary Scores
schizophrenics.
episode
admitted
DSM-III (Endlcott
with
a mean age of
five
males
psychosis
controls
of
Treatment of
interview
and
using
diagnostics. 1978). 27.2
and for There
?: 8.3
and one female
had occurred
Unit
Cincinnati
7 months
were
(mean
with
a mean
to
11 years
CSF CCK. psychosis
?: 3.4 years)
(5.2
prior
(except
for
an 8:00
AM lumbar
Study
lorazepam
Following
least
In the for
schizophrenics.
behavioral
recovery
of
Each had been
control)
for
at
least
drug
free
14 days
prior
to
CSF.
responders.
”
trial
responded
achieve
of
to
were
to
to
free
respond
haloperidol
the modified
at baseline
response”
(number
baseline
of
more fully
days
showed
a 55% improvement
having
an “early
failed
to
responded
Assessment
discontinued
the
haloperidol
periods
times
weekly
treatment for
CCK levels.
(1988).
scores
to haloperidol.” response
time
of
until
of
the
et
In less
than
to achieve
more than
28 days
from
the
the
of
so as to
1984)
were
The “latency 55% reduction
with could
are
and who
be described
schizophrenics
facility;
for
described
haloperidol
haloperidol
as
either
treatment
such
of of
schizophrenic protocol
18 days of
who had
scores
al
response.
treated
The remainder
a
dose-adjusted
(Zemlan of
“lithium
Patients
Paychoels
clinical
patients
transfer/discharge to
rate
the
be discharged
and began
haloperidol-treated
Details
Schizophrenic
from baseline
(NBSI)
necessary
each
were
levels
during
considered
dose.
35 days.
determine
lithium
lithium
trial
up to
treatment
therapeutic
who could
were
In divided
Index
to
to
patients
symptoms
by day 14 of
or non-responders
withdrawn
with
the
from
hospitalized
in
collection
were
assayed
the
“late
Only
at
or had
schizophrenfds
are
haloperidol.”
Instruments
was
samples
al
response
at
as
alone.
15 mg/day
for
alone
response
psychotic
alone
a standardized
lithium
at
was determined
show comparable
described
lithium
haloperidol
CSF
et
to
plasma
of
baseline
in Garver
on lithium positive
of
substantial
New Raven Schizophrenic
scores)
with
showed
of
received
a trial
beginning
and three
psychosis
comparisons
in (RIA)
reacts
with
indication
the
tubes
kept
the
assay
those
continued
patients
with
patients
haloperidol
assessed
the
If
9 It 2 ng haloperldol/ml
according
CSF
beginning
virtually
who failed
therapeutic
schizophrenic
1988)
days.
they
alone,
Patients
al
twelve
two week trial,
of
for
studies,
et
on lithium
not
study
intermittently
puncture
baseline (Garver
at
not
the
603
response
Design
protocol for
to
and antipsychotic
lateral
Immediately and patients
at
until
-7O’C
laboratory et
1981)
CCK-33 and CCK-8, of
bimodal
from
closer
to
the the
were
shipped
at M Beinfeld al
but
distribution patients
position
immersed
controls
(Beinfeld
data
decubitus
fails of
in dry
St.
ice
detect
CSF CCK in
was performed
to
in one ml aliquots,
at bedside.
In an identical
for
Louis
7 & 8 of to
ice-methanol
performed
on dry at
on mls
at L4 or L5 level
assay.
Immunoreactive
University
the
using
CSF tap.
unsulfated the
CCK-8.
patients
a CCK radioimmuno-
Though
fully there
patients, with
The CSF CCK was
The antibody
schizophrenic
contrast
Collections
manner.
lowest
crosawas no
a median CCK
split
values
controls.
Data Analysis Significance statistic Spearman
for rank
of
differences
independent method
(rs).
between samples.
subject Significance
groups of
was evaluated correlations
with were
the Mann-Whitney
assessed
with
the
vs.
604
M.C.BeinfeldandD.L.Garver
Results CSF CCK in Schizophrenicsand Controls Mean drug-free CSF CCK levels were 15.5 ? 4.5 pmol/ml (range 6.9 - 23.4 pmol/ml) In the schizophrenics and 27.4 ? 5.1 pmol/ml (range 19.8 - 33.0 pmol/ml) in the controls (MannWhitney a'= 3.02; p < 0.002). as shown in Fig 1.
Interestingly,male schizophrenicshad
lower CSF CCK levels than females, 12.7 + 3.4 pmol/ml vs. 18.9 f 3.05 pmol/ml (MannWhitney z - 2.37; p < 0.01). The single female control had a CSF CCK value (29.4) similar to that of control males (27.0 ?:5.7 pmol/ml).
26 0
0
p
