Co-administration of sertraline and haloperidol

MIN-SO0 LEE,hlD. CHANG-SU HAN,~ID,YOUNG-\VOONYOU,h l D AND SEUNG-HYUN KIM, h1D

Dcparfiiinlt of Pqdiiatry, Collqc of.\ fcdicirie, Korrri Uirir*rr.+, Seoiil, Korea

Abstract Along with recent increased interest in the selective serotonin reuptake inhibitors, a number of studies has been
undertaken to observe interactions with different drugs.\Vhen selective serotonin reuptake inhibitor was adniinis-
tered together with antipsychotics to schizophrenics showing depressive or obsessive symptoms and negative
synipton~,meaningfiul results were observed.The objective of our research was to identify the changes in the con-
centration o f plasma haloperidol when sertraline was administered to patients who already were being treated with
haloperidol. Sixteen patients who did not respond to tlie traditional antipsychotics after 2 \veeks of treatment with
a certain dosage ofhaloperidol were adnlinistered with 50 mg ofsertraline for a period o f 2 weeks.The concentration
changes between plasma haloperidol and the reduced haloperidol were observed using high-powered liquid chro-
niatography equipped with a U V detector.There was a significant increase ( P < 0.01) in the concentration of halo-
+
peridol, the change being from 8.52 4.22 to 10.91 & 5.38 ng/niL. However, the change in the conceiitration of
reduced haloperidol was from 7.41 f.7.93 to 5.22 f.6.10 ng/mL, showing a sipificant decrease.The concentrations
of tdtal plasma haloperidol showed n o significant changes at all. I n comparing the ratio of the reduced haloperidol
and tlie haloperidol, the reduction ratio \vas down to 0.39 k 0.27 from 0.94 f.0.65 showing a significant decrease.
There seerils to be few studies done o n interactions using serotoriegic d r u g together with antipsychotics in spite of
their clinically applicable possibility.According to similar studies done in the past. co-administering of such d r u g
not only increases the plasma concentration of antipsychotics, but it also results in clinical improvement of negative
symptoms and aggravation of extrapyramidal symptoms. Changes in clinical symptoms and adverse effects were not
observed in our study. However, we think these observations need to be included in upcoming larger scale studies.
Key words co-administration, haloperidol, reduced haloperidol, sertnline.

INTRODUCTION
In neuropsychiatric clinical treatment, whenever we come across
chronic schizophrenics who d o not respond favorably to tndi-
tional antipsychotics, we usually consider the co-administering
ofmedicines as an alternative clinical approach.This type ofalter-
native approach or strategy not only has a wide scope of clinical
applications but it is also well known for its high level of effec-
tiveness. Although co-administering of various medicines o r
polypharmacy has been considered undesirable clinical treatment
in the past, administering antipsychotics together with tricyclic
antidepressant to the patients showing psychotic depression is
recognized as a first-line clinical treatment nowadays.'
In the case of schizophrenics who d o not respond to anti-
psychotics and in whom negative symptoms are dominant,
co-administering tricyclic antidepressant and antipsychotics
attracts much attention and research work is active. T h e litera-
ture study by Siris and others shows that although there was
significant iniprovenient in the depressive symptoms, it appeared
that there was not much effect o n other psychotic symptoms
when tricyclic antidepressant was co-administered to schizo-
phrenics who were being treated with antipsychotics.* Followed
by these kinds ofresearch results, there has been a recent research
that administered a serotonin reuptake inhibitor, fluoxetine
instead of tricyclic antidepressant together with antipsychotics
to schizophrenics?.'
Correspondence address:hlin-Soo Lee, ~ I L ) . 126-1, j-K~.Ananl-Dong, Sungbuk-
Ku.Seou1 136-705, Korra.
Although there mere not many patients who were adminis-
tered with tlie treatment, the result of the research was encour-
aging as it proved that the treatment brought favorable
improvenients in positive and negative symptoms and in depres-
sive symptoms. Even though there are not enough theoretical
bases for explaining these clinical changes, it can be based on
pharmacological and pharmacodynaniic changes and much
attention needs to be paid to the influence affecting the sero-
tonin system.
Recently, there has been increased interest about the function
of various neurotransniitter systems in addition to the dopaniine
hypothesis in relation to the e t i o l o g and symptoms of schizo-
phrenia. Previously, niost research had focused on the positive
symptoms caused by the excessive dopanune and consequently
treatments with antipsychotics which \vork as barriers to
dopanline receptors were prevailing, but there were many cases
that did not respond to negative symptoms. There were also
various constraints in the treatment of schizophrenics due to the
problenls of unavoidable extrapyranlidal side effect symptoms. I n
recent years, however, there have been new attempts in observa-
tions and studies on the etiology and symptoms of the schizo-
phrenics based on the development of biological psychiatry and
in the development of medicines. Especially, there have been
numerous research papers reported on the actions o f the sero-
tonin system. Among these, there is, first of all, research on
5-hydroxyindole acetic acid (5-HIAA) of cerebrospinal fluid.
According to this research 5-HIAA \vas increased among schizo-
phrenics who have historical f31ilily trends, chronic course,
problems in physical movements, while there was decrease in
S194
5-HIM among patients who had trends of violence and hyper-
sensitivity and among those who showed expansion of lateral
ventricle of cerebrum in the cross-section photograph of tlie
brain?.6 It is known that excessive serotonin in tlie central ner-
vous system may cause a state of negative symptoms of schizo-
phrenics and it has close interrelationship with behavioral
problems such as suicidal b e l i a ~ i o r . ~
According to research on peripheral blood, the interpretation
of tlie cross-sectional brain photograph showed that there were
contractions of the cerebrum cortex and expansion of ventricle
among the schizophrenic groups who had increased concentra-
tion of serotonin in the blood? It was also reported in another
study that implied the interrelationship between the depressive
symptom and serotonin and the symptonis of anxiety and
depression were accompanied when there was low 5 - H I M
concentration.'
Upon studying these kinds of research results, Bleich and
others proposed a hypersensitivity theory of 5-hydroxytrypta-
n i n e type 2 (5-HT2) receptor on the interrelationship between
schizophrenics and serotonin systeni." Besides, there'are many
research results reported that range from the research in the
suspension effects of lysergic acid diethylamide (LSD), a hallu-
cinogen, which brings similar symptoms as schizophrenics to the
research in the alleviating action ofthe serotonin depleter on the
symptoms ofschizophrenics." Based o n these studies, there have
been increased interests in new antipsychotics and their clinical
effects, and new drugs that act only on the serotonin systeni
were developed.There are ritanserin, a selective 5-HTz antago-
nist, risperidone and ondansetron, 5-HT2 and D2 antagonists,
and ondansetron, 5-HT2 antagonist is also under development.'*
It is quite difficult to use antipsychotics which act to the pre-
viously mentioned serotonin system as first-line medicines for
tlie patients who d o not respond to the traditional psychotropic
medicine, especially for those who show negative symptoms. It,
therefore, can be said that co-administering with traditional
antipsychotics and serotonergic antidepressant is an effective
treatment strategy we need to pay attention to.
There has not been any research in Korea o n the effects of
co-administering serotonergic antidepressant and classical anti-
psychotics o n the syniptoms of schizophrenics which are being
attempted overseas these days and we undertook this study in
order to obtain basic data o r information o n what kind of
changes this co-administering of drugs can bring about from the
point of clinical and pharniacological aspects. In this research, we
only attempted to observe and examine the changes of plasma
haloperidol concentration; upon co-administering serotonin
reuptake inhibitor, sertraline, and haloperidol, and the study o n
the changes in clinical effectiveness will be attempted in the
future comprising a larger pool of target patients including con-
trol groups.
Although the serotonin reuptake inhibiting effect of the
sertnline, which is one ofthe recently introduced selective sero-
tonin reuptake inhibitors, is similar to that of the other serotonin
reuptake inhibitors, it is generally known that there are sigii-
ficant discrepancies in the aspect of pharniacology. Especially,
the inhibiting effect o n tlie hepatic nietabolizing enzyme cyto-
chronic P450 IID6 (CYP2D6) which interacts in the biological
transfer and pharmacological actions is only 15-20% of tlie sero-
tonin reuptake inhibitors. There is a report that the sertraline
M-S. Lce ct al.
barely affected tlie blood concentration, while the fluosetine
and parosetine reduced the desipramine cleannce rate up to
400% when esperiniented with a model of desipramine and
they brought about a significant blood concentration increase."
Based o n these studies, we examined the changes of the
plasnia haloperidol concentration which could b e introduced by
the co-administering ofthe sertraline, a selective serotonin reup-
take inhibitor, to the chronic schizophrenics w h o were being
treated with haloperidol.
MATERIALS AND METHODS
Sixteen patients, who were classified as chronic schizophrenics
according to DSM-111-R diapostic criteria,'+were chosen from
patients w h o were being treated at Daenani Mental Hospital in
Pusan from March to August in 1993 to be the target groups.
Hospitalization was inevitable for the 16 patients chosen as their
symptoms did not improve even though they were administered
with sufficient dosages of antipsychotics for more than 6 months.
Before the inclusion in the research target group, they were ad-
ministered with the sanie level of haloperidol dosage (2-3.5 mg/
day) for at least 2 weeks and co-adninistering of other medi-
cines was avoided except minimal aniounts of benzodiazepine
niesylate. Of the 16 patients chosen, 11 (68.75%) were male and
five (31.23%) were female, the avenge age was 37.69k9.05.
years and the average bodyweight was 61.63 k 6.00 kg. The
average duration of illness of the patients was 11-73 k 7.72 years
and the average daily dosage of the medicine per unit body-
weight was 0.24 k 0.16 nig/kg as their daily average dosage of
the medicine \vas 11.88 f 9.56 nig.
Research m e t h o d
Administering the haloperidol for all subjects was done once a
day at 20.00 h maintaining constant individual dosage for 2
weeks and 10 cc of blood sample was taken from each patient at
08.00 h dailyThereafter, they were co-administered with 50 mg
of sertraline and haloperidol at 20.00 h for 2 weeks and at the
end of 2 weeks 10 cc of blood was taken at 20.00 h from each
patient. T h e blood samples were kept in lithium-heparin tubes
and they were centrifuged for 20 niin at tlie speed of3000 r.p.m.
within 1 h from the tinie they were taken.The separated blood
plasmas were kept in sealed polypropylene tubes at the tenipera-
ture of 2OoC until they were analyzed.
Method of m e a s u r i n g plasma haloperidol and
plasma-reduced haloperidol
T h e concentrations of the plasnia haloperidol and plasnia-
reduced haloperidol were measured using a modified method of
that used by Dhar and Kutt."
High-porrrred liquid clrrorriatopphy q ~ p a w t m
For analysis of high-powered liquid chromatography (HPLC),
model 305 pump, model 117 variable wave length UV detector,
and ASTED (Automated Sequential Enrichment of Dialysates)
system equipped with Rheodyne 7.01. injection valve (Gilson
Inc.) were used and the chromatography data were analyzed by
using an IBM PC which was equipped with 712 HPLC system
controller software connected with 506C interface module. As
Co-administration of sertraline and haloperidol s133

for the column analyzer, 2501.6 nini I.D., 5 ni particle size,
reversed phase C-18 colunin (Rainin Inc.) was used.
Rcosqerrts nrrd stnrrdnrd so/ritioru
All reqerits risen were p d e d rrsed&r nrrnlysis yrrryoses: potassium
phosphate (nionobasic), heptanesulfonic acid, triethylaniine and
isoaniyl alcohol were from Sigiia Inc.; acetonitrile was from E M
Science; hesan was from Baker Inc. and the distilled water used
was triple distilled, produced by Mill Q reagent n w e r systeni
(Millipore). For standard solutions, we used haloperidol supplied
by Sigma Inc., reduced haloperidol by Janssen, and broniperidol
by Hanwha Inc.The solutions were prepared with a concentra-
tion ratio of 1mg/niL in 0.1 N HCI solution and mere kept at a
temperature of -70°C.\Vhenever they were needed they were
unfrozen and diluted.
Coriditiorufor arinlysis nrid nrialyzirlg rriethod
A total of 2 m L of plasma, 100 ng of Internal Standard (broni-
peridol) and 500 pL of 1 N N a O H were put into a 15 mL
polypropylene tube, and after 1 niin of vortes mixing, 5 niL o f
hexan containing 1.5% isoaniyl alcohol (v/v) was added into the
tube.After 20 niin ofconcussion and 15 min of3000 r.p.m. cen-
trifugal process, 1mL of the upper level fluid w a s taken fmni the
tube and the fluid taken was put into another t1ibe.A total of
200 pL of 0.1 M HCI was added to the fluid and after another
20niin o f concussion the fluid was centrifuged.
The fluid produced by the centrifugal process was separated
carefully and 50 mL of the separated fluid was injected into the
HPLC system.
The mobile phase was composed of 0.05 M KHzPO, and
acetonitrile at the ratio of 60:40 and lmniol/L of sodium
heptanesulfonic acid was added to make 0.01 niol/L triethy-
lamine. After the mixing, p H 4.0 was set by using phosphoric
acid and it ~ 3 used
s after filtering with 0.15k nini pore size
filter and degassing. T h e wavelength of the UV detector used
was 214 nni, sensitivity was 0.005 Auk and the speed of the fluid
current o f the mobile phase was maintained at 1.0 mL/min.
The margin of measurement of the plasma haloperidol and
reduced haloperidol using the above method was 1 ng/niL and
the recovery rate was 60-70%.The concentration was obtained
form the peak height displayed o n the chromatography with the
use of Internal Standard Reagent Calculation Method.
Stntistic dnto treofrrierrt
Data analysis was done using Statistical Package for Social
Science-Personal Computer (SPSS-PC) version -1.0 1- T h e con-
centration of haloperidol and reduced haloperidol in the plasma
before and after the administering of the sertraline was verified
with paired f-test.The correlation between the aniouiit of halo-
peridol dosage per unit ofbodyweight and the concentrations of
plasma haloperidol and plasma-reduced haloperidol, and the
reduction ratio (the ratio between the plasma-reduced halo-
peridol and plasma haloperidol) were analyzed using Pearson’s
nionient correlation coefficiency analysis.The significance level
of the statistical treatment results was set at P < 0.05.
RESULTS
The concentrations o f haloperidol and reduced haloperidol
measured in the plasma of the research target patients are shown
inTable 1.The correlation between the daily haloperidol dosage
per unit bodpveight and the concentrations of the plasma
haloperidol and reduced haloperidol, measured before co-
administering with sertraline, showed statistical significance as it
was espected; in the case of plasma hiloperidol concentration

Table 1. Demographic data and haloperidol concentration

No. Sex Age Bodywcight Dose O f Hal* Hall Ha12 Red-H1 Red-H2
(years) 0%) (nig/day) (ng/mL) (ng/”’L) (ndmL) (ng/mL)

1 F 34 59 27 0.46 11.80 5.80 6.19

2 M 37 69 30 0.43 17.90 3.30 G.00
3 F 29 51 12 0.24 6.80 3.30 3.40
4 F 38 74 21 0.28 13.40 6.00 6.20
5 M 35 64 12 0.19 7.96 2.84 3.61
6 M 30 58 18 0.31 11.44 1.56 3.53
7 M 32. 5s 35 0.60 30.97 33.84 23.87
8 M 37 63 15 0.24 9.56 5.61 1.76
9 M 43 66 15 0.23 16.35 18.02 13.40
10 M 67 62 3 0.05 6.19 4.67 1.15
11 hl 38 60 12 0.20 7.17 4.84 1.02
12 M 42 56 2 0.03 3.04 3.65 0.68
13 F 19 57 15 0.26 19.56 7.82 9.26
14 h.1 39 65 10 0.15 9.34 5.44 1.42
15 hl 30 66 3 0.05 4.62 5.27 1.02
16 F 40 55 8 0.15 8.47 6.72 1.08
*,Daily dose of haloperidol; **, daily dose of hnloperidol/bod}~~ci~ht;
Hall, plasma haloperidol conccntration at baseline; Hal?, p13SIll3 haloperidol conccn-
tration after adding scrtraline;Rcd-Hall , plasnin-rcduccd hdopcridol concentration at baseline; Rcd-Hal?, plasnia-rcduccd hdopcridol concentration after
adding sertraline.
S196 M-S. Lee ct d.

the Pearson's r \vas 0.71, and in the case of plasma-reduced reduced haloperidol concentration sho\vs no significant changes,
haloperidol concentration Pearson's r as 0.55 (Figs 12). being 16.06 k 10.34 and 16.25 k 11.01 ng/niL, respectively,
T h e average concentration of the plasma haloperidol upon when measured before and after co-administering of sertraline,
co-administering with sertraline was increased significantly to as shown inTable 2.
10.91 k 5.48 ng/mL from the pre-co-administering levels of
8.52 k 4.22 ng/mL (Table 2). 0
When the changes of plasma haloperidol concentration were
drawn together with the daily haloperidol dosage per unit body-
\\.eight, following co-administering of the sertraline, me may see L

an ascended recurrent straight line as shown in Fig. 3. The

plasma concentrations of reduced haloperidol, when compared C
before and after administering sertraline, were reduced signi- c)
0 y=0.7271+27.7825~ R=0.55. p=0.014
ficantly and they were 7.41 k 7.93 and 5.22 f 6.10 ng/mL,
C

-0
0 20 -
respectively (Table 2). z?
If the changes of plasma-reduced haloperidol concentration
L
a
Q.
15 -
\vere drawn together with the daily haloperidol dosage per unit -
0
m
r
bodynxight, following co-administering of sertraline, we may -0
0
10 -
see a descended recurrent straight line as shown in Fig. 4. 3
D
The reduction rate which shows the ratio between the
5- "
0
??
plasma-reduced haloperidol and the haloperidol was signifi- m 0 Ip
E
cantly reduced from 94.46 k 65.90 to 39.07 k 27.42% with the In
m 1 m
co-administering of sertraline (Table 2). T h e concentration of h o r . 1 . 1 . I ' I * I ' I - t
0.0 0.1 02 0.3 0.4 0.5 0.6 0.7
total plasma haloperidol concentration, which is an arithmetic
Daily doses of haloperidol (rnglkg of body weight)
addition of the plasma haloperidol concentration and the
Figure 2. Relationship benveen plasma reduced haloperidol concentra-
tions and daily doses of haloperidol at baseline.
181 y= 3.8914 f 19.2441x e0.71, p= 0.01
T
.
E 16
cn
K
14
C
.-0
12
c
c
8
c
10
0
0
0 8
.-
D
L

g 6
0
-
rJ
S
a 4
:
2 2
R

-0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 7

Daily doses of haloperidol (rnglkg of body weight)

Figure 1. Relationship benveen plasnia haloperidol co~icentratio~i~

and Figure 3. Changes of plasma haloperidol coticentratio~i~ after adding
daily doses of haloperidol a t baseline. sertraline. A Hall, plasma haloperidol concentration at baseline; A Hal?,
plasnia haloperidol concentration after adding sertraline.
Table 2. Changes ofplasma haloperidol concentration

Plasma concentration Baseline haloperidol alone Second \veek combined sertraline Pd u e

Hal (ng/niL) 8.53 f 4.22 10.91 f 5.83 0.004

Red-ha1 (ng/niL) 7.12 f 7.91 5.22 2 6.10 0.021
Reduction ratio* 91.46 f 65.90 39.07 2 27.12 0.003
Total ha1 ( n ~ / m L ) 16.05 f 10.34 16.25k 11.01 0.s15
*, plasma-reduced haloperidol/plastiia haloperidol; **, plasma-
Hal, plasma haloperidol concentrations; Red-hal, plasma-reduced haloperidol co~iceiitratio~is;
reduced haloperidol + plasma haloperidol; ***,paired 1-test.
Co-adniiriistration of sertraline and lialopcridol
Y = 0.72713 + 27.782~ r=0.55
r=0.79
0.0 0.1 02 0:3 0:4 015 06 0:7
Daily doses of haloperidol
(rnglkg of body weight)
Figure 4. Changes of plasnu reduced haloperidol concentrations after
adding sertraline. A Red-H1, plasma reduced haloperidol concentration at
baseline;A Red-H?. plasnin reduced haloperidol concci~trationafter adding
sennline.
DISCUSSION
Sertraline (lS, 4s-A'-methyl-4 (1,2,3,1-diclophenyl)-I,2,3,~-
tetnhydro-lnaphthalenaniine) is a strong and selective reuptake
inhibitor. It is absorbed relatively slowly in the gastrointestinal
tract. Its reduction time is 3211 and the duntion of time for
reaching its highest in plasma is 6-8 h. It takes approximately 7
days to restore its stabilized states. Its biological utility n t e is 50%
and it has high level of lipid solubility, while its rate of fusion
.with plasnia protein is nearly 95%.
The nietabolisni of the sertraline takes places mainly in the
liver and it undergoes a process of deniethylation. During nieta-
bolic period, desciiethylsertnline is produced as 3 priniary
metabolic product and it is in a biologically activated state.
However,it has been reported that sertraline has only about 10%
of effectiveness in serotonin reuptake inhibition effectiveness
showing alniost no pharmacological actions due to its low lipid
solubility.'6
Based on research outcomes on the reciprocal interactive
action with other medicines, it is observed that in the case of
antipyrine the removal was accelerated, while diazepam and
tolbutamide reduced the removal. However, in the case of
lithium, desipramine, digosin, atenolol etc., they did not affect
anything."-19 Sertraline acts as a weak derivative nietabolisni in
the activation of hepatic niicrosomal enzyme and its virtue is
approsirnately one-third of that of phenobarbital.'*
It was also reported that the efficacy of reciprocal action with
other medicines was caused mainly by inhibiting hepatic metab-
olizing enzyme CYP2DG, and it is also known that this kind of
action ofsertraline is very much insignificant compared with the
selective serotonin reuptake inhibitors such as fluosetine or
parosetine?O T h e pharmacological characteristic of haloperidol,
which is co-administered together with sertraline, is similar to
that of CYP2DG as it is already known, and it acts competitively
with the inhibiting actions of the sertraline for this enzyme.
In this study, there was a significant increase in the changes of
average haloperidol concentration followed by co-administering
and it w a s increased fmni 8.53 k -1.22 to 10.91 ? 5.39 ng/niL. If
S197
converted into percentage, it is approsiniately 28% and this
suggests that pharniacological interaction is relatively weak.
This result sho\vs that tlie outconie of the experiment is
similar to the result of studies by Goff ef d."and Ames er a!.' who
investigated the changes of haloperidol concentration after co-
adniinistering haloperidol and fluosetine to schizophrenics.
Although there were not many target patients in the study by
Goff et A!., it proved aggravation of estnpynniidal symptoms
which was accompanied with favorable improvements in both
positive and negative schizophrenic symptoms."
The foundation of tlie estrapynniidal symptoms is not clear,
but the changes in the clinical symptoms and side effects may
be caused either by an increase in the plasma haloperidol
concentration o r by the direct effect of increased activities of
the serotonin nervous systeni to the dopamine systeni. Similarly,
Baldessarini and Marsh observed the inhibition of catechol-
aniitie composition only when there was sufficient dopaniine
in mammalian cerebrum by administering fluosetine to animals,
and based o n this they proposed that serotonin causes inhibiting
effects o n the dopaniine neuron.*' Nevertheless, in spite of
numerous research outcomes affecting estrapynniidal symptoms,
it is considered that there is ;I need to pursue more neuro-
physiological and pharmacological statistics on the detailed
foundations.
We consider different methods of applications in the treat-
ment of schizophrenics depending o n their clinical situations
because most of the traditional medications have merits and
demerits. We may consider co-administering of antipsychotics
together with antidepressants when patients do not respond to
antipsychotics o r when schizophrenics accompany partial obses-
sive o r depressive symptoms. Especially, by co-administering
serotonergic drugs we may espect direct effects o n the central
nervous system in addition to the pharmacological synergy
effect. As already mentioned, there was a study by Siris et d. in
which n o other clinical effects were caused except the improve-
ment of depression when tricyclic antidepressant was adminis-
tered together with antipsycliotics.22This is a contrasting result
with the result that comes from the co-administration of sero-
tonin reuptake inhibitors.
First, it is necessary to consider metabolic aspects ofmedicine
and look at tlie differences between the so-called 'fast nietabo-
lizer type' and 'slow nietabolizer type' since there are individual
differences in the metabolic rates. It is observed that tlie slow
nietabolizer types, who have reduced the level of biochemical
activity of the medicinal metabolic enzyme CYP2D6 (debriso-
quin h y d r o q h e ) , are found in the majority of Caucasians while
the fast nietabolizer types who have higher levels of enzyme
activities, although there is no accurate statistical data, generally
exist aniong many Oriental people. Therefore, in this research,
we could assume that there was a significant level of increase in
the plasma haloperidol in spite of the low CYP2DG inhibition
rate of ~ertraline.2~
Second, upon co-administering of sertraline, the concentm-
tion of reduced haloperidol was reduced from 7.41 k 7.93 to
5.22 k 6.10 ng/mL and this was a significant reduction which
contrasted with the significant increase in haloperidol. This
result also contradicts the observation results of the fluosetine
co-administration research by Goff et A ! . ~
S198
Reduced haloperidol is the major metabolizer of the
haloperidol and it is a h y d r o y haloperidol metabolized through
an oxidative i\’-dealkylation process of the piperidine nitrogen.
It is known that the lipid solubility of this is similar to that of
haloperidol and that its plasma concentration is 6-300%.
What is interesting is that together with an advocacy these
kinds of metabolizers, although small, have pharniacological
effects, and there is research which states that people w h o have
high plasma concentration barely respond to treatment.” There
is another study which reports that the reduced haloperidol
and haloperidol are intertransferable by hepatic metabolizing
enzyme P430 and during this process the individual differences
bring about individual differences in the effectiveness o f medi-
cines? In spite of the fact that haloperidol has less active nieta-
bolic substances and its metabolism is so simple that it can
become a most suitable sample in observing the treatment effec-
tiveness and dosages, there is still room for controversy and there
remains the need for further detailed study o f this.
It is considered necessary to identi@ the cause of the differ-
ences benveen our results and other similar results. There are
some important points we need to consider in performing this
kind of experiment: tlie sensitivity of quantitative medicine
analysis method; selection of appropriate patients; maintenance
of administering constant quantity of medicines; utilization of
double blind method; control of variables according to age
and gender, and selection of accurate o r appropriate statistical
methods etc.26
In this research, we observed the interaction from pharmaco-
logical points of view by investigating the changes in halo-
peridol concentration with co-administering sertraline. It is our
opinion that obtaining more detailed data o r inforniation would
have been possible if investigations on the schizophrenic synip-
toms and the existence of side-effects were conducted concur-
rently with this research.
CONCLUSION
We observed the effects o n the plasma haloperidol concentra-
tion and its nietabolic substance, plasma-reduced haloperidol
concentration upon co-administering 50 m g of selective sero-
tonin reuptake inhibitor, sertraline, to 16 schizophrenics who
had been undergoing treatment with constant dosage of halo-
peridol for more than 2 weeks.
Upon co-administering with sertraline for 2 weeks the aver-
age concentration of the plasma haloperidol was significantly
increased to 10.91 f 5.48 from 8.52 t 4.22 ng/mL. In the niean-
time, tlie average concentration of the plasma-reduced haloperi-
do1 was reduced to 5.22 f 6.10 from 7.41 & 7.93 ng/mL.
There was insignificant changes in the total concentration of
plasma haloperidol (addition of concentration of the reduced
haloperidol and the haloperidol).The change was from 16.06 k
10.34 to 16.26 k 11.01 ng/niL.
T h e changes in the reduction rate resulting from 2 weeks of
sertraline co-administering showed a significant reduction from
94.46 k 65.90 to 39.07 k 27.42%.
Although the changes in the clinical symptoms caused by the
co-administering of medicines were not measured in this
research, it is considered necessary to investigate the effects on
M-S. Lee PI 01.
the positive and negtive syitiptonis of schizophrenics and tlie
side-effects concurrently with this sort of research in the future.
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