EUROPEAN NEURO.

PSYCHOPHARMACOLOGY
ELSEVIER
European Neuropsychopharmacology 6 (1996) 85-91

Response in chronic schizophrenia correlated with chlorpromazine, 7-OHchlorpromazine and chlorpromazine sulfoxide levels
M. Chetty a'*, V.L. Pillay b, S.V. Moodley c, R.
Miller d
~Department of Pharmacy, Wits University Medical School, 7 York Road, Parktown 2193, South Africa hDepartment of Chemical Engineering, University of Natal, Durban, South Africa ~Fort Napier, Pietermaritzburg, South Africa dDepartment of Biopharmaceutics, Food & Drug Administration, Washington, DC. USA
Received 26 June 1994; accepted 4 July 1995

Abstract
The relationship between chlorpromazine, six of its metabolites and therapeutic response in chronic schizophrenic patients was investigated in this study. Logistic regression revealed no correlation between therapeutic response and four metabolites viz. Nor, chlorpromazine, Nor 2 chlorpromazine, chlorpromazine-N-oxide and Nor 2 chlorpromazine sulfoxide. A good correlation was seen between CPZ (P=0.036), 7-hydroxychlorpromazine (P=0.004), chlorpromazine sulfoxide (P=0.002) and therapeutic response. Good therapeutic response was correlated to high levels of chlorpromazine and its 7-hydroxy metabolite while high levels of the sulfoxide metabolite appeared to have a negative effect on therapeutic response. Poor responders who had high levels of chlorpromazine also had high levels of the sulfoxide metabolite. This suggests that the difference in response may lie in the difference in the metabolism of the drug.
Kevwords: Chlorpromazine; Metabolite; Therapeutic effect

1. Introduction
The clinical efficacy and safety of chlorpromazine (CPZ) may be enhanced by evaluation of its plasmaconcentration-effect characteristics but little information is presently available on these properties of CPZ. Many authors have reviewed studies that have attempted to correlate levels of CPZ and its metabolites with clinical outcome in schizophrenics (May and Van Putten, 1978; Cooper, 1978; Midha et al., 1987; Cohen, 1984; Baldessarini et al., 1988; Dahl, 1986; Balant-Gorgia et al., 1993). However, most of the evidence on plasma-concentrationeffect relationships of CPZ have been inconclusive and controversial. In a critical review, May and Van Putten (1978) have ascribed the failure to establish a definite correlation between plasma concentration and effect to factors such as technical problems in obtaining and preparing the chemical analysis of plasma samples; heterogeneity of population samples with regard to age, acuteness or chronicity of disease, and duration of neuroleptic treatment; lack of distinct and specific clinical end points; lack
*Corresponding author. Fax: 011-6472052. 0924-977X/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0 9 2 4 - 9 7 7 X ( 9 5 ) 0 0 0 4 7 - X

of a sensitive clinical psychiatric scale and the rote of CPZ metabolites. With the shortcomings of previous studies in mind, this study was designed to investigate whether any correlation exists between plasma concentrations of CPZ, the major metabolites of CPZ and therapeutic response, in chronic schizophrenic patients who had relapsed and were treated with variable doses of CPZ (as determined by the psychiatrist in attendance).

2. Research methodology
2.1. Patients

Ethical approval for this study was obtained from the University of Durban-Westville. In-patients between the ages of 16 and 55 years with a diagnosis of schizophrenia (American Psychiatric Association, 1987), from the King George V Hospital and Fort Napier Hospital were included in the study. Informed consent was obtained from the patient, guardian or the medical superintendent. Patients presenting with an or-

4. 1988). Rockville. Any dosage change was made at least 5 days prior to the blood level being taken. Factor score sum of composite items number of composite items The scores. administration of another antipsychotic agent or if the patient developed severe or unacceptable adverse reactions to CPZ. 10 ml of blood was drawn from the median cubital vein of the patients weekly (for 3 weeks). and the coefficients for logistic regression were estimated. Pharmacodynamic assessments Response to CPZ therapy was assessed by the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham. Relapsed patients were included provided CPZ or its metabolites were not present in the plasma on admission to hospital.K. Thereafter the BPRS assessment was performed weekly. renal or gastrointestinal disease. / European Neuropsychopharmacology 6 (1996) 85-91 ganic disorder. Stepwise logistic regression (multiple logistic regres- 2. For each set of variables (metabolites) considered. 7-Hydroxychlorpromazine (7-OH-CPZ) Nor I chlorpromazine (Nor~CPZ) Nor 2 chlorpromazine (Nor2CPZ) Chlorpromazine-N-oxide (CPZ-N-OXIDE) Chlorpromazine sulfoxide (CPZ Sulf) Nor 2 chlorpromazine sulfoxide (Nor2CPZ Sulf) The sensitivity for CPZ was 3 ng/ml. a continuous variable (e. in the study. Dosage adjustment was based on the clinical judgement of the psychiatrist in attendance. The BPRS assessments were made by the patients' therapist. This method of data analysis was used to assess the frequency of patients responding (coded as 1) or not responding (coded 2) to varying plasma concentrations of CPZ and the metabolites. Kennedy of the National Institute of Mental Health. to establish the absence of detectable levels of CPZ or its metabolites in plasma prior to inclusion in the study. plasma concentrations of three metabolites) is added to or removed from the model. predicted probability. Logistic regressions of therapeutic response versus plasma concentrations of CPZ and six metabolites were carried out in this study. the change in log likelihood from the previous step and three goodness-of-fit chi-square statistics. when blood samples were taken. stepwise logistic regression was also used. Thereafter. No other concurrent medication was permitted. Some patients were given anticholinergic medication at the request of the psychiatrist. to ensure that steady state was reached. The patients were given sugar coated CPZ tablets. Logistic regression 2.~ n The model is fitted to the data using the maximum likelihood ratio technique for the binomial distribution of response or outcome. plasma concentrations of CPZ and concentrations of six different metabolites). At each step in the stepping process. 2. 2. In the first step the log transformed concentrations of chlorpromazine and each of the metabolites were calculated and each of these was used separately in a logistic regression. as assessed by product-moment correlation. 1962). The BPRS factor score described below was used in the pharmacodynamic assessment (Overall and Gorham. A baseline assessment was performed on inclusion . Heparinised tubes were used and contact with the rubber stopper was prevented. with the assay sensitivity for each metabolite given in square brackets. plasma concentration of a metabolite) or a set of variables (e. [3 [5 [4 [5 [4 [6 ng/ml] ng/ml] ng/ml] ng/ml] ng/ml] ng/ml] The synthetic metabolites were supplied by Dr S. the output includes frequency of success or failure. The technique is termed logistic regression because it investigates the linear dependence of the logistic transformation of the dependent variable (outcome or response) to several independent variables (plasma concentrations) (Kirkwood. hepatic. Blood sampling Blood samples were drawn from the patients on entry into the study.g. The logistic transformation (abbreviated as logit) is defined as: proportion Logit = log e i . The patient was withdrawn if there was evidence of non-compliance. 1988). e. USA and Prof. The output includes the log likelihood. Plasma concentration analysis Plasma samples were stored at -70°C and analysed by normal phase high performance liquid chromatography (HPLC). 1991). The metabolites that were measured are listed below. was shown to be favourable prior to commencement of the study.2.g. Routine physical examination and clinical laboratory tests were performed on admission of the patient. observed proportion and standardized residuals. predictor (independent) variables were selected in a stepwise manner. Inter-rater reliability testing.86 M.5. as described previously (Chetty and Miller. 12 h after the evening dose. rated by the clinician.g.3. Since there were many independent variables (time. ranged from 1 (symptoms not present) to 7 (symptoms extremely severe). K. were excluded from the trial. Cheto' et al. The step selections were based on the maximum likelihood ratio. Using this technique. Midha of the University of Saskatoon.

The relationship between these plasma concentrations and therapeutic response can be represented by the following equation: exp( . response to CPZ therapy decreases and higher concentrations of CPZ and 7-OH-CPZ are required to produce a response with a probability greater than 50%.contributed independently to the outcome.27 + 3. the contour in Fig. The results of many studies that have attempted to correlate the CPZ metaholite levels with therapeutic response to CPZ therapy concur with the observations made in this study. hostility.2160 0.0362 0. and r = 0. Results Thirty patients of Asiatic origin were included in this study.0037 0.48(1n M2) pr . Correlations were considered to be significant when P<0. conceptual disorganisation and tension. CPZ-N-OXIDE and Nor 2 CPZ Sulf (Table 2). All the above logistic regression analyses had time as a co-variant factor.5) and viewed from above. One patient withdrew his consent to participate in the study a week after he had been included.85.27 + 3.002 for the following items: emotional withdrawal. Inter-rater reliability testing (assessed by product-moment correlation) produced the following favourable results: r=0.001 for the following items: somatic concern. guilt feelings.5 decreases ie. P<0.g. the area representing pr>0.03. la is a graphical representation of the probability of response relative to all three components for the final regression model with one of the components.5-91 Table 1 Demographic characteristics Number of patients Number of samples Age (years) Weight (kg) Male Female Dosage range (mg/day / 29 87 16-50 48-81 18 12 300-1200 87 0.18(1n C P Z ) + 2. NorICPZ. / European Neuropsychopharmacology 6 (1996) 8. viz. motor retardation.0362). r=0.71.M.. If the line corresponding to pr=0. mannerisms and posturing.67. Results of logistic regression revealed no correlation between therapeutic response and four metabolites. Discussion The results of this study suggest that the therapeutic outcome of CPZ therapy is influenced by the parent compound as well as two of the metabolites that were measured viz. consisting of plasma concentrations of CPZ and the metabolites and BPRS scores. Contours similar to that in Fig.386(1n MI ) .e. SAS Institute Inc.4. P<0. blunted affect.0017) and therapeutic response. unusual thought content. CPZ Sulf (P= Table 2 Results of logistic regression Drug CPZ CPZ-N-oxide 7-OH-CPZ CPZ Sulf Nor~ CPZ Nor2CPZ N o h C P Z Sulf P value 0. l b is obtained.5032 Fig.e. This graph illustrates that for a given concentration of CPZ Sulf (e. A good correlation was seen between CPZ (P=0.03 for the remaining three items. SAS software (version 6. pr=0. that were used in the logistic regression analysis. suspiciousness. Chetty et al. The 87 sets of data. P<0.0037).11. grandiosity. lc.48(1n M2)) where: pr sion-backward elimination) was then used on all the above variables to determine which ones . 7-OH-CPZ (P=0. 50 ng/ml) the probability of CPZ treatment producing therapeutic improvement in 50% of the patients (i. 4.e. unco-operativeness. contour representing P=0. In Fig.5) will depend on the relative concentrations of CPZ and 7-OH-CPZ. CPZ Sulf.4. l b for CPZ Sulf concentrations ranging from 5 ng/ml to 125 ng/ml are presented in Fig.2230 0.1 + exp( . The demographic characteristics of the patients are presented in Table 1. depressive mood.18(In C P Z ) + 2. are given in Appendix 1. i.05. l b the area above the curve represents the combinations of concentrations that would produce a >50% probability of improvement. North Carolina) was used to analyse data by logistic regression. In M1 In M2 In CPZ exp =probability of therapeutic response =natural logarithm of the concentration of 7-OH-CPZ =natural logarithm of the the concentration of CPZ Sulf =natural logarithm of the concentration of CPZ = exponent 3. fixed at 50 ng/ml.0017 0.11. These contour plots illustrate that as the concentration of CPZ Sulf increases. NorzCPZ. CPZ Sulf and 7-OH-CPZ. hallucinatory behaviour.5 is highlighted in Fig. la (see line i. In a study of eight male schizophrenics treated long-term with high doses of CPZ (700-5000 . anxiety.386(1n MI) . Increasing concentrations of 7-OH-CPZ and CPZ were associated with therapeutic improvement while increasing concentrations of CPZ Sulf were associated with diminished therapeutic response.6025 0.

~ d ~ e~ ~ a a ~ ~lllan ~ a ~ W > 0.5 i 1 Fig+ 1.5 contmw ~ pr (b) . Chetty et al.c (c) 10 1Q0 20o 300 400 500 600 f 4nm to i~ii.\.88 M. / European Neuropsychopharmacology 6 (I996) 8 5 . . Graphical representation of the probability of response.. s? .9 t (a) p = o.

the non-responders had levels of CPZ Sulf that were greater than their CPZ levels whereas the responders had lower levels of CPZ Sulf (Sakalis et al. The ratio of 7-OH-CPZ/CPZ Sulf was significantly greater in well controlled patients than in poorly controlled patients. The CPZ Sulf concentrations were significantly lower in the good response group compared to those showing poorer control. K. poor responders who had high levels of CPZ also had high levels of CPZ Sulf. These researchers found that small quantities of blood catalyse the formation of chlorpromazine sulfoxide from CPZ in a dose-dependent manner in vitro. Carlile for his assistance in the design and initial implementation of the protocol. Appendix I Plasma concentrations of CPZ. 1976. In a review on the plasma level monitoring of antipsychotic drugs. Sakalis et al. This suggests that the difference in response in chronic schizophrenics may lie in the difference in the metabolism of the drug.. 7-OH-CPZ and CPZ Sulf in 86 chronic schizophrenic patients. 1973. is the target receptor in the brain occupied by a pharmacologically inactive metabolite which acts like a competitive antagonist or a partial agonist? Does a high concentration of CPZ Sulf effect changes that may modulate responsiveness of the D 2 receptor to the active compounds? Does CPZ Sulf exert its inhibitory effect on therapeutic improvement via another receptor such as the D 3 receptor? Why do some patients have higher CPZ Sulf/CPZ ratios than others? Traficante et al.. Cooper (1978) attributed the absence of 7-OH-CPZ in the above studies to technical difficulties in the assay procedure rather than the absence of the metabolite in the plasma of the patients. Chetty et al. it is probably too complex to be useful in routine therapeutic monitoring of the drug. Here again CPZ Sulf appeared to be the 'inactivating' metabolite. (1974) when they reported that the CPZ Sulf to CPZ ratio appeared to be higher in the unchanged group of schizophrenics (nine patients) when compared to the slightly improved (10 patients) and improved (seven patients) groups. 1976). 1977) examined the ratios of 'active' and 'inactive' compounds in responders and nonresponders. Curry. This study was conducted at the University of Durban-Westville. These findings are similar to those of the present study. However. (1972. National Institute of Mental Health for supplying the test samples of CPZ metabolites. some patients had relatively high levels of CPZ but failed to show good therapeutic response.M. Mackay et al. (1979) have focused on the last question when they suggested that sulfoxidation of chlorpromazine by human blood may represent a major metabolic route of drug inactivation in humans. Midha of the University of Saskatchewan and Dr S. Such patients are usually classified as being resistant to CPZ therapy. Good response was correlated to lower CPZ Sulf/CPZ ratios and higher 7-OH-CPZ/CPZ ratios. Although the above studies have provided a compelling body of evidence associating high concentrations of 7-OHCPZ with therapeutic improvement and high concentrations of CPZ Sulf with diminished improvement. The findings of Sakurai et al. / European Neuropsychopharmacology 6 (1996) 85-91 89 mg/day). The proposed therapeutic window for CPZ is 30-350 ng/ml (Rivera-Calimlim et al. This lends further support to the findings of the present study. The 7-OH-CPZ levels were higher in the good response group compared to those showing poorer control. Kennedy of the U. The concentration of CPZ was not significantly different in good and poor responders. some researchers (Phillipson et al. The assistance of the nursing staff at the King George and Fort Napier Hospitals is appreciated.B.S. The authors are also grateful to Dr J. 1973. The negative effect that high concentrations of CPZ Sulf appear to have on therapeutic improvement raises the following questions which warrant further investigation: In the case of poor responders.K. (1974) examined the relationship between global symptom control and plasma concentrations of CPZ. The observed relationship between plasma drug and metabolite concentrations and therapeutic outcome is very interesting to the researcher and the clinician. Measuring plasma CPZ Sulf levels relative to CPZ and 7-OH-CPZ levels may be useful in patients who do not show good response to CPZ. 1973). However. This agrees with our finding that high levels of CPZ Sulf are associated with diminished therapeutic response. Good responders had ratios of CPZ+7-OHCPZ to CPZ Sulf that were greater than 1 while poor responders had ratios lower than 1. An endogenous inhibitory protein 'regulates' sulfoxidation in vivo. High concentrations of CPZ Sulf relative to the other two compounds may warrant the change of the drug rather than a dosage increase. the metabolites and therapeutic response . In this study a good response was associated with CPZ levels of 30 ng/ml to 380 ng/ml. Further preliminary studies by these researchers have suggested that schizophrenic patients who do not respond to CPZ and have high plasma levels of ring-sulfoxide appear to have much lower levels of this endogenous plasma protein factor than those patients who are known drug responders. Acknowledgments The authors would like to thank the Medical Research Council (SA) for the Research Grant and Prof. perhaps due to a particular subtype of schizophrenia. In this study.. (1975) supported those of Mackay et al. 1977) were unable to detect 7-OH-CPZ in both good responders and poor responders.

71 30.60 9.50 024 49.00 24.47 53.00 65.57 64.51 13.00 76.00 17.00 47.7t 148.64 42.26 25.00 55.14 17.61 102.00 15.14 26.85 BD 4.73 82.00 126.56 115.07 143.90 72.06 10.93 50.71 12.00 13.13 8.80 84.00 19.78 50.00 BD BD 7.00 53.00 19.64 11.00 14.19 23.26 38.04 68.88 138.51 90.28 5.42 22.23 31.71 15.22 172.03 47.47 62.53 36.53 324.69 29.26 28.17 9.00 19.16 36.00 33.07 107.83 81.47 15.00 17.95 17.60 91.2.41 13.09 19.41 5.4 91.30 53.54 83.25 22.51 58.92 172.58 10.42 11.00 16.10 331.11 11.24 25.51 23.04 53.31 43.67 19.53 50.60 19.28 8.38 93.84 1 t.10 80.00 42.37 20.34 157.79 27.05 24.90 21.00 26.95 7.19 55.32 187.27 25.00 6.18 9.53 35.03 17.32 31.23 14.63 18.67 21.95 51. I 0 13.58 t 6.85 89.35 6.87 13.25 18.38 14.50 493.08 54.10 15.45 57.73 19.44 90.22 33.00 46.00 7.45 155.73 86.44 29.40 138.19 t 8.40 274.24 CPZ Sulf 84.74 42.85 24.62 18.08 28.01 23 2 8 6~00 9.53 118.16 4.90 80.00 10.52 61.24 8.00 29.14 1 t .70 50.44 35.00 27.47 BD 64.82 8.13 5.50 12.45 121.00 93.39 77~81 49.60 309.30 68.20 22.79 84.36 1 t .00 13.86 21.44 122.00 41.31 59.91 32.26 60.25 73.25 20.60 83.00 46.36 18.90 11.00 81.99 7.80 36.15 158.18 37.42 134.60 18.84 40.85 16.58 BD 47.56 19.68 19.23 BD 78.03 7.21 18.00 t 6.60 11.20 9.10 89.00 220.11 13.48 18.54 422.51 50.00 BD 8.85 33.32 42.56 17.00 24.00 125.15 5.83 23.95 45.10 t 03.49 479.78 96.96 8.98 21.14 5.41 13.90 40.00 49.74 Patient 1 1 1 2 2 2 3 3 3 4 4 4 5 5 5 6 6 6 7 7 7 8 8 8 9 9 9 I0 10 10 11 11 11 12 12 12 13 13 13 14 14 14 15 15 15 16 16 16 17 17 t7 t8 18 t8 19 19 19 20 20 20 21 21 21 22 7-OH-CPZ 24.18 2.21 17.00 241.70 283.18 95.12 20.22 479.04 69.32 66.22 17. / European Neuropsychopharmacology 6 (1996) 85-91 Concentration (ng/ml) CPZ CPZ-N-OXIDE 89.25 62.88 13.20 29.32 68.27 89.53 15.97 43.82 10.49 20.98 18.74 53.65 53.48 39.64 197.60 36.43 65.36 50.97 121. Chetty et at.68 2.53 107.37 I9.90 23.52 32.95 45~00 26.29 30.51 21.50 9.37 20.52 30.36 BD BD 16.96 48.96 BD BD BD 0.00 46.00 381.82 143.62 10.20 42.51 22.50 121.83 BD 115.59 2Z40 16.71 12.80 28.18 40.0I 11.00 32.27 5.73 23.00 59.30 26.33 BD 64.60 47.69 19.50 67.10 159.34 t 59.33 60.58 18.98 61.15 214.21 28.29 14.06 NOR2CPZ Sulf 4.81 16.70 34.53 56.40 221.00 20.10 33.00 15.00 66.84 173. t 5 12.00 82.15 15.69 62.44 34.40 127.14 28.90 25.76 37.80 21.29 15.81 74.38 5.27 94.50 85.82 3!.60 5.85 82.96 14.05 22.2 I t 6.00 21.00 62.10 170.55 14.00 37.99 14.00 37.74 28.00 10.25 71.89 36.32 51.59 145.73 21.53 13.84 100.53 43.23 97.68 57.82 69.86 125.18 16.70 31.00 1 t.20 Time (weeks) Response .72 22.90 220.26 30.00 9.00 59.51 l 1.49 23.20 28.01 33.30 31.83 8.90 M.01 40.00 61.84 BD 24.04 12.96 5.53 24.86 17.54 125.45 49.95 30.65 32.74 40.60 55.02 39.89 87.0O BD BD NOR~CPZ 30.05 44.11 25.19 79.52 21.18 62.52 66.5 t 174.48 14.76 36.90 168.27 29.38 52.94 27.90 68.73 18.70 NOR2CPZ 69.30 7.05 28.93 10.66 51.81 26.34 12.40 32.84 121.07 35.08 41.87 20.00 33A4 43.99 39.35 t 9.57 t 79.80 165.49 BD t 2.00 47.67 12.30 127.54 6.21 142.99 BD 19.23 254.37 21.50 13.68 53.95 40.53 t8.20 16.16 12.63 52.00 89.83 27.96 51.

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