Open Journal of Psychiatry, 2012, 2, 262-268 OJPsych
http://dx.doi.org/10.4236/ojpsych.2012.24036 Published Online October 2012 (http://www.SciRP.org/journal/ojpsych/)
Relationships between clozapine and norclozapine plasma
concentrations, clozapine dose, and clinical response in
Tunisian patients with schizophrenia-treatment resistance
Aida Taieb1,2*, Fatma B’chir3, Roland Molinié1, José-Edmundo Nava-Saucedo1, Jaafer Nakhli4,
Marc-André Fliniaux1, Bechir Ben Hadj Ali4, Saad Saguem2
1Unit of Plant Biology and Insect Pests, University of Picardy Jules Verne, Amiens, France
2Metabolic Biophysics and Applied Pharmacology Laboratory, Department of Biophysics, Medicine Faculty of Sousse, Sousse, Tunisia
3Laboratory of Natural Substances, National Institute of Research and Physical Chemical Analysis, Technopole Sidi Thabet, Tunis,
Tunisia
4Psychiatry Department of Central Hospital University (CHU), Sousse , Tunisia
Received 20 April 2012; revised 26 May 2012; accepted 7 June 2012
ABSTRACT
The present study investigated relationships between
clozapine dose, clozapine and norclozapine plasma
concentrations, and clinical responses to clozapine
treatment in Tunisian schizophrenics. Fourteen schi-
zophrenia-treatment resistant patients, recruited for
this study, were treated with clozapine for 45 days.
Patient health improvement was assessed before and
after each cycle of two weeks of clozapine therapy,
using the Brief Psychi atric Rating Scale (BPRS). Pl asma
clozapine and norclozapine concentrations were deter-
mined by high-performance liquid chromatography
(HPLC). No significant correlations between plasma
clozapine and norclozapine concentrations and clini-
cal health improvement among our schizophrenic
patients were found. However, a significant correla-
tion was observed between clinical health improve-
ment given by BPRS scores and norclozapine plasma
concentration to daily clozapine dose ratio (NCZ/D).
Despite the small sample size of our study, our find-
ings suggest that the clozapine therapy response va-
riations observed in our patients may be, in part, ex-
plained by the interindividual differences in plasma
norclozapine concentration to clozapine dose ratio
(NCZ/D). So the NCZ/D parameter could be used as a
good indicator for adjusting the clozapine dose-adap-
tation strategy and consequently for improving the
clinical psychopathological state of schizophrenia-treat-
ment resistant patients.
Keywords: Clozapine; Norclozapine; HPLC; Tunisian
Schizophrenic; BPRS
1. INTRODUCTION
Clozapine (CZ) is a second-generation antipsychotic drug .
It is primarily used in the treatment of schizophrenia-
treatment resistant psychopathology. However, treat-
ment with clozapine is associated with several side ef-
fects that complicate the use of the drug and necessitate
therapeutic monitoring [1,2]. This monitoring allows the
optimization of the therapeutic dose-response efficacy
and the prevention of excessive toxicity of CZ, reducing
in this way the risk of relapse [3-5]. Despite the effec-
tiveness of clozapine as a standard drug for schizophre-
nia-treatment resistance, important individual variations
in the response to clozapine therapy were reported
[6,7].
The mechanism underlying the differences in clozap-
ine treatment response is not well known. Some studies
attribute t hese differences to patient s’ sex, age, body weight,
and physiology [8]. Other studies suggest that these vari-
ations are related to the plasma concentrations of cloza-
pine and its active metabolite, norclozapine [9], with the
explanation that monitoring plasma clozapine concentra-
tions may play a useful role in the management of pa-
tients with schizophrenia. Moreover, it may be possible
that the metabolic polymorphism of clozapine elimina-
tion, attributed to genetic and/or environmental origins,
modifies clozapine plasma concentration and elimin ation
and thus its psychotherapeutic effects.
Therefore, this study has been undertaken to explore
possible correlations between clinical responses to cloza-
pine and parameters such as clozapine and norclozapine
plasma concentrations, clozapine clearance, clozapine
metabolic index, and norclozapine plasma concentration
to daily clozapine dose ratio. Our interest is in offering
some explanations for the interindividual variability of
*Corresponding a uthor.

A. Taieb et al. / Open Journal of Psychiatry 2 (2012) 262-268 263
clozapine therapy response.
2. MATERIALS AND METHODS
2.1. Patients
Fourteen patients with schizophrenia-treatment resistance
were recruited for this study. These patients were com-
posed of 3 males and 11 females aged 19-62 years and
were taken from the psychiatric department of the Uni-
versity Hospital Centre (CHU) Farhat Hached of Sousse
(Tunisia). The diagnosis of schizophrenia-treatment resi-
stance was established by the DSM-IV (Diagnostic and
Statistical Manual of Mental Disorders) criteria for schi-
zophrenia [10]. The physical characteristics of the pati-
ents are given in Tab le 1. All the patients in this study
were treated with CZ, and they did not take any other
associated treatment.
The fourteen patients selected for this study represent
35% of the total number of cases treated in the hospital
of Sousse and 14% of the total cases of schizophrenia-
treatment resistance in Tunisia. The population of this
country is over one million inhabitants. Treatment-resi-
stant schizophrenics represent only 0.01% of the popu-
lation. Thus, the fourteen patients recruited to this study
are enough representatives for a local-level study, but not
for a global approach.
This study was carried out in the biophysics laboratory
at the Faculty of Medicine. The ethics committee of the
Faculty of Medicine approved the study, and each patient
provided informed consent.
2.2. Clinical State Assessment
The effectiveness of treatment for the psychopathological
state was determined by the Brief Psychiatric Rating
Scale (BPRS). The BPRS estimations obtained before the
treatment with CZ and during the therapy period were
reported in our study as health improvements and ex-
pressed in percentages. A BPRS value is determined be-
fore the application of the treatment and a new BPRS
value is determined after the treatment (45 days later).
The final BPRS value is given by the equation: ([BPRS
before treatment-BPRS after treatment]/BPRS before
treatment) × 100 [11].
2.3. HPLC Plasma Analysis and Clozapine and
Norclozapine Concentrations
The schizophrenic patients recruited into the study were
given clozapine at a dosage of 100 - 900 mg/day for 45
days. Blood samples were drawn from each patient 12
hours after the last intake of the CZ dosage at the end of
each cycle of 15 days over a period of 45 days.
Blood samples were immediately centrifuged at 1800
g for 15 minutes at 4˚C, and the plasma samples collected
Table 1. Physical characteristics of 14 schizophrenic patients.
PatientGenderAge (years) Weight (Kg) Height (m)
(a) W 35 60 1.58
(b) W 39 60 1.60
(c) W 43 70 1.69
(d) M 40 95 1.77
(e) W 42 88 1.75
(f) W 62 76 1.65
(g) M 19 69 1.70
(h) M 33 83 1.73
(i) W 22 70 1.62
(j) W 23 74 1.65
(k) W 19 62 1.65
(l) W 48 80 1.65
(m) W 40 62 1.62
(n) W 29 62 1.65
were stored at –20˚C until the time of an alysis. The con-
centrations of CZ and NCZ were assessed by the High-
Performance Liquid Chromatography (HPLC) method
develope d by Shen et al. [12], with some modifications.
The separation of these analytes was performed using
reverse phase HPLC (Agilent 1200). A volume of 5 µL
of prepared plasma was injected into the analytical
column (C18 ODS, Agilent type) maintained at a tem-
perature of 30˚C. The elution was maintained in isocratic
mode with a mobile phase consisting of water, acetoni-
trile, and N,N-dimethyloctylamine (62.6:37:0.4). The
elution flow rate was 1 mL·min–1. The analytes were de-
tected at a wavelength of 280 nm. Plasma clozapine and
norclozapine concentrations were calculated by Chem-
station software using preestablished calibration curves.
2.4. Measurement of Clozapine Metabolic Ratio
Norclozapine is the main metabolite of clozapine. The
metabolic pathway from clozapine to norclozapine is me-
diated mainly by the hepatic CYP1A2 enzyme.
The measurement of the concentration ratio of no rclo-
zapine to clozapine (NCZ/CZ) was used as a metabolic
marker to evaluate CYP1A2 activity and therefore the
elimination profile of CZ.
2.5. Measurement of Clozapine Clearance
Clozapine clearance was determined by the ratio of clo-
zapine dose (D) intake to clozapine plasma concentration
(D/CZ).
2.6. Statistical Analysis
Regression analysis was used to find correlations be-

A. Taieb et al. / Open Journal of Psychiatry 2 (2012) 262-268 264
tween the different parameters studied and the BPRS
scores (health improvement of patients). Analyses of
variance (ANOVA) and t-tests were used to test corre-
lations between clozapine and norclozapine plasma con-
centrations, clozapine metabolic index, and norclozapine
plasma concentration to daily clozapine dose ratio as
well as percent improvement in BPRS scores.
3. RESULTS
3.1. Association between CZ and NCZ Plasma
Concentrations, CZ Clearance, and BPRS
Score
The plasma concentrations of CZ and NCZ were deter-
mined for a period of 45 days at the end of each two-
week cycle. The mean values of CZ and NCZ plasma
concentrations (±90% confidence intervals), CZ clea-
rance, and clozapine dose intake for each patient as well
as percentage BPR S scores are given in Table 2.
There is large intervariability in CZ mean plasma con-
centrations, ranging from 120 to 1304 ng·mL–1 for all
patients. This wide variation was also observed for the
NCZ mean plasma concentrations.
The CZ plasma concentration parameter, which is used
as an indicator of the treatment response and dose adap-
tation, shows no significant correlation with the health
state improvement given by BPRS scores (r = 0.0989; p <
0.737) (Figure 1).
For example, patient (a) who presents with severe
toxicity (agranulocytosis) has a BPRS value of 7.3% and
a CZ plasma concentration measure of 1280 ng·mL–1,
whereas similar levels of plasma CZ concentration, such
Table 2. CZ, NCZ, D/CZ values and BPRS scores of 14
schizophrenic patients.
Patient CZ (ng/mL) NCZ
(ng/mL) D (mg/day) D/CZ (L/h) BPRS (%)
(a) 1280 ± 292 42 ± 10 400 13 7.3
(b) 120 ± 27 27 ± 4 300 104.218.5
(c) 1203 ± 198 127 ± 39 400 13.9 20
(d) 843 ± 492 228 ± 76 900 44.5 22.9
(e) 710 ± 695 123 ± 85 400 23.5 26.9
(f) 120 ± 20 36 ± 11 100 34.7 31.9
(g) 495 ± 51 173 ± 43 650 54.7 32.5
(h) 499 ± 121 145 ± 46 500 41.8 35.6
(i) 1304 ± 784 214 ± 91 550 17.6 42.4
(j) 1080 ± 330 194 ± 34 500 19.3 50
(k) 618 ± 679 140 ± 19 400 27 53
(l) 650 ± 63 150 ± 28 400 25.6 54.2
(m) 1145 ± 172 158 ± 28 400 14.6 54.9
(n) 950 ± 73 181 ± 29 500 21.9 68.8
0 102030405060708
0
200
400
600
800
1000
1200
1400
0
plasma clozapine concentration (ng/ml)
BPRS score (%)
r = 0.0989; p < 0.737
Figure 1. Relationship between BPRS scores and plasma levels
of clozapine.
as 1304 and 1145 ng·mL–1, were found in patients (i) and
(m) who had higher BPRS values of 42.4% and 54.9%,
respectively.
Furthermore, although the BPRS values of 53% and
54.2%, respectively, for patients (k) and (l) were found to
be similar to those of patients (i) and (m), their corre-
sponding plasma CZ concentrations of 618 and 650
ng·mL–1, respectively, were very low compared to those
found in patients (i) and (m).
The estimated CZ plasma clearance values (D/CZ)
ranged between 13 and 104.2 L·h–1. Statistical analysis,
illustrated in Figure 2, showed no significant relation-
ship between response to clozapine treatment, assessed
by BPRS scores, and CZ plasma clearance (r = 0.32; p <
0.265). Of the fourteen schizophrenic patients in the
study, four had BPRS scores falling within a narrow
range (50% to 54.9%), whereas they showed a wide
range of CZ plasma clearance values (14.6 to 27 L·h–1).
Furthermore, patients (l) and (m), who had practically
the same BPRS score (ca. 54.55%), showed different
clearance values of 25.6 and 14.6 L·h–1, respectively.
3.2. Association between NCZ/CZ Ratio and
BPRS Scores
Table 3 shows wide variations for all patients in NCZ to
CZ ratio, which expresses CYP1A2 activity, ranging from
3.3% to 35%. These variations suggest wide interindi-
vidual differences in CYP1A2 activity.
Statistical analysis did not provide any significant
association between the NCZ/CZ ratio and the BPRS
values (r = 0.167; p < 0.569). For example, an approxi-
mate ratio value of 22.8% was found in patients (k) and
(l) along with higher BPRS scores of 53% and 54.2%, re-
spectively, whereas the same ratio value was found in
patient (b) who had a lower BPRS value of 18.5%.

A. Taieb et al. / Open Journal of Psychiatry 2 (2012) 262-268 265
0 10203040506070
0
20
40
60
80
100
120
clozapine clearance values (L/H)
PBRS scores (%)
r = 0.32; p < 0.265
Figure 2. Relationship between BPRS scores and clozapine
clearance levels.
Table 3. NCZ/CZ values and BPRS scores in 14 schizophrenic
patients.
Patient NCZ/CZ (%) BPRS (%)
(a) 3.3 7.3
(b) 22.5 18.5
(c) 10.6 20
(d) 27 22.9
(e) 17.3 26.9
(f) 30 31.9
(g) 35 32.5
(h) 29 35.6
(i) 16.4 42.4
(j) 18 50
(k) 22.6 53
(l) 23 54.2
(m) 13.8 54.9
(n) 19.1 68.8
3.3. Association between NCZ/CZ Ratio and
BPRS Scores
The NCZ plasma concentration to CZ dose ratio value
(NCZ/D) was calculated for each patient. The ratios
ranged from 7.8 to 34 s·L–1. There was a significant
linear correlation (t calculated value = 4.20; t0.05 = 2.18)
between the NCZ/D ratio and the BPRS levels (r = 0.77;
p < 0.0012).
Figure 3 shows the estimated regression line (y = 12.3 +
0.38x; r2 = 0.6) with the centroid (NCZ/D ratio and
BPRS score means), the experimental values, the confi-
dence band borders, and the prediction band borders. The
prediction band is useful for making presumptions about
a minimum B PRS level attained for a max imum NCZ/D
ratio value.
4. DISCUSSION
In this preliminary study, we have tried to give some ex-
planations for the large interindividual response varia-
tion to clozapine therapy observed in Tunisian schizo-
phrenic patients.
We have noted that the improvement in the psych-
opathologic state of schizophrenic patients differs from
one patient to another for the same clozapine dosage.
Multiple parameters have been measured in th is study,
as well as their relationships with the therapeutic effec-
tiveness of CZ in schizophrenic patients.
The results show that no significant correlations were
found between clinical health improvement in Tunisian
schizophrenic patients and these measured parameters,
namely plasma clozapine and norclozapine concentra-
tions, clozapine metabolic ratio, and clozapine clearance.
This result leads us to suggest that none of these pa-
rameters can be used as standard biomarkers for assess-
ment of the therapeutic efficacy of clozapine [13,14].
Although there is cons iderable variability in daily drug
treatment, a significant correlation between clinical
health improvement, given by BPRS scores, and norclo-
zapine plasma concentration to daily clozapine dose ratio
(NCZ/D) was recorded. A wide variability in plasma CZ
levels following intake of a large range of drug doses
was observed in our patients. In fact, patients with a
daily drug dose of 400 mg showed higher plasma CZ
concentrations than other patients taking a daily dose of
900 mg. So these differences in CZ plasma concentra-
tions between patients may not be associated with dif-
ferences in dose intake but rather with metabolic poly-
morphism under the influence of environmental and ge-
netic factors [15,16].
In this respect, particular attention has been focused on
plasma drug concentration monitoring as a potential tool
for determining the probability of achieving a satisfac-
tory response [17]. However, there is controversy regard-
ing the relationship between CZ pl asm a level s and psycho-
pathologic state improvement. Some studies confirm an
apparent relationship between plasma clozapine levels
and its psychotherapeutic effect [6,9].
But other studies contradict these positive results [17-
22]. These findings are in close agreement with our re-
sults showing no association between plasma CZ concen-
tration and amelioration of psychopathologic state in pa-
tients with CZ-treatment resistant schizophrenia.
Our findings in this study reported no significant rela-
tionships between clozapine metabolic ratio, clozapine
clearance, and clinical health improvement in Tunisian
schizophrenic-treatment resistant patients.
These results are consistent with those reported by
Chong et al. and Doude van Troostwijk et al. [7,23], as
are our results on the potential role o f NCZ to CZ ratio as
a parameter providing the optimal clozapine-treatment

A. Taieb et al. / Open Journal of Psychiatry 2 (2012) 262-268 266
Figure 3. Correlation between plasma norclozapine concentration to clozapine dose ratio (NCZ/D) and clinical re-
sponse (BPRS). Regression line parameters: y = 12.3 + 0.38x, pReg < 0.0012, pbo < 0.0056, pb1 < 0.0012; r2 = 0.6
(Determination coefficient); r = 0.77 (Correlation coefficient). (BPRS) = [(NCZ/D) – 12.3]/0.38 (Prediction equation
for the BPRS).
response and those results reported by Palego et al., Jerl-
ing et al. and Mauri et al. [24-26] showing that cloza-
pine plasma clearance was not significantly associated
with the therapeutic efficien cy of the drug.
The second reason is about the difficulty of explaining
the significance of this relationship from a biological
viewpoint. According to its expression, it represents the
plasma concentration of norclozapine per unit dose of
clozapine administered. But, as a result, it also represents
the relationship of the metabolic ratio (NCZ/CZ) to the
plasma clearance of clozapine (D/CZ).
A significant relationship between the norclozapine
plasma concentration to clozapine dose ratio (NCZ/D)
and the response to treatment, evaluated by the BPRS
levels, was found in this study (Table 4). Our results
suggest that the norclozapine plasma concentration to
clozapine dose ratio (NCZ/D) could be used as a good
indicator for improving the clozapine dose-adaptation
strategy.
Plasma clearance indirectly brings into play all of the
processes involved in the plasma filtration of clozapine.
Its catabolism by CYP1A2 assessed by the metabolic
ratio constitutes one of these processes. It is conceivable
und er these conditions that the NCZ/D relationship which
also represents the relationship of the metabolic ratio to
the clearance, allows the assessment of the relative im-
portance of the filtration processes of clozapine with the
exception of the metabolic filtration of CYP1A2. The
NCZ/D relationship would be as low for a given me-
tabolic ratio, as the filtration processes involved (with
the exception of those relating to CYP1A2) are impor-
tant.
As a result, this parameter (NCZ/D) appears to be a
plasma marker adaptable to a collective scale unlike
other parameters (plasma concentration of clozapine, clo-
zapine metabolic ratio) which can only be considered on
an individual scale (Table 4).
However, this result, as important as it is, must be
taken with caution for at least two reasons. The first re-
lates to the limited number of patients in the sample
recruited for this study of the existence of a significant
correlation between the NCZ/D relationship and the
BPRS score. Validation of such a result would indeed
require a greater number of schizophre nics analyzed.
It seems possible that the negative results observed in
our study, particularly the association between the con-
centration of drug in plasma and its effects on the im-
provement of the psychopathologic state, may be related

A. Taieb et al. / Open Journal of Psychiatry 2 (2012) 262-268 267
Table 4. Association between measured parameters and clinical health improvement in 14 schizophrenic patients.
Measured parameters Clinical health
improvement Comments/recommendations
Clozapine plasma
concentration BPRS
There is no correlation between these two parameters. However, plasma concentration of
clozapine appears to be an important parameter, both to individually assess the therapeutic
interval thresholds at the start of treatment and also to ensure medical follow-up relative to
the regularity of taking medications.
Clozapine metabolic
ratio (NCZ/CZ) BPRS
There is no correlation between the metabolic ratio values and the BPRS scores. It is noted,
however, that patient (a) is the only one whose ratio value plummeted, showing CYP1A2
enzyme activity of almost zero. It must be noted that not only is the BPRS score of this
patient the lowest (7.3%), but it is also the only patient who developed severe toxicity
expressed by the appearance of agranulocytosis leading to the termination of clozapine
treatment. Overall, if our results show that the metabolic ratio value of clozapine is not a
marker assessing therapeutic efficacy, they nevertheless suggest that a ratio of almost zero
related to very low CYP1A2 activity may constitute a risk factor of developing severe
toxicities during clozapine treatment.
Clozapine clearance
(D/CZ) BPRS Our results indicate that plasma clozapine clearance cannot constitute a standard marker for assessment of the therapeutic ef ficacy of clozapine.
NCZ/D BPRS
There was a significant correlation between clinical health improvement, given by BPRS
scores, and norclozapine plasma concentration to daily clozapine dose ratio (NCZ/D). Such
a result is important insofar as it constitutes an attempt at establishing therapeutic standards
based on clozapine. It is in fact the relationship of the metabolic ratio to the clozapine
clearance. Our results show that the therapeutic efficacy of the drug would be as great as
the value of this parameter is high and no matter which patient is being considered.
to the small sample size of the study and the heterogen-
eity of the recruited patients—the majority of our popu-
lation consists of women. It was reported that sex may
have a great influence on health psychotherapeutic im-
provement [8].
Moreover, it has been proposed that there is a close
association between the genetic polymorphism of various
genes involved in the metabo lism and receptor regulatio n
of anti-psychotic drugs.
So in future investigations, a large and homogeneous
sample is needed to characterize in more detail the re-
lationship between clozapine pharmacokinetic parame-
ters and their antipsychotic effects, in order to explain
the wide variation in clozapine-treatment responses ob-
served in schizophrenic patients.
5. ACKNOWLEDGEMENTS
The authors would like to thank all the individuals who participated in
this study.
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