HUMAN PSYCHOPHARMACOLOGY , VOL. 8,133-1 39 (1 993)

A Study of the Therapeutic Spectrum of a Fixed-dose of Zotepine and its Relationship with Serum Concentrations of the Drug TSUYOSHI KONDO*, KOICHI OTANI, MASAYUKI ISHIDA, KAZUO MIHARA, OSAMU TANAKA, SUNAO KANEKO and YUTAKA FUKUSHIMA Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, 036 Japan

The therapeutic spectrum of zotepine, an antipsychotic drug, and its relationship with serum concentrations of the drug were investigated by a fixed-dose study (100mg/day in the first week, and 200mg/day for the next 3 weeks) in 20 schizophrenic in-patients. The mean percentages of symptom reduction in total Brief Psychiatric Rating Scale (BPRS) and three subgroups were 63.4 per cent for total, 64-4 per cent for positive symptoms, 41.8 per cent for negative symptoms and 74.2 per cent for anxiety-depression respectively. Total, positive and negative symptoms were significantly reduced after 2 weeks (p < 0-OI), while a significant reduction in anxiety-depression symptoms was already found after 1 week (p < 0.01). There were significant differences in the values of percentage improvement in total and positive symptoms after 2 weeks (p < 0.05) and negative symptoms after 1 week (p < 0-05) between responders (more than 50 per cent reduction in total BPRS scores at the end of the study) and nonresponders. In 18 patients (90 per cent), the clinical response at 2 weeks corresponded well to the final outcome. No definite relationship was found between serum zotepine concentrations and the clinical efficacy.

KEY wow-Zotepine, schizophrenia, therapeutic spectrum, serum concentrations.

INTRODUCTION Zotepine is an antipsychotic drug developed in Japan, and has been used in the treatment of schizo- phrenic and acute manic patients. The clinical effi- cacy of this drug for paranoid schizophrenia has been shown to be comparable to those of conven- tional antipsychotic drugs, e.g. haloperidol (Fleischhacker et al., 1989) and has fewer extrapyr- amidal side-effects than haloperidol (Fleischhacker et al., 1989; Barnas et al., 1992).

The antidopaminergic effects of zotepine were reported to be equivalent to those of chlorproma- zine in animals (Uchida et al., 1979). However, its antiserotoninergic property is much more potent than chlorpromazine (Yamawaki, 1987), suggest- ing that zotepine has some additional therapeutic effects compared with conventional antipsychotic drugs. In fact, relatively low doses of zotepine have been reported to be effective for the treatment of negative symptoms in schizophrenics (Barnas et al., 1992). Nevertheless, few data are available on the precise therapeutic spectrum of zotepine.

Several studies have shown significant relation- ships between plasma concentrations of antipsy-

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* Author to whom correspondence should be addressed.

chotic drugs and clinical response (Dysken et al., 1981; Bolvig Hansen and Larsen, 1985; Van Putten er al., 1992) while no definite relationship could be found in other studies (Van Putten et al., 1981; Volavoka et al., 1992). Previously, we studied the steady-state serum kinetics of zotepine. We found that there is a large inter-individual variation in the metabolism of this drug, and that smoking enhances, while co-adminstration of benzodiaze- pines may inhibit, its metabolism (Otani er al., 1993). However, it is unknown whether zotepine has an optimal therapeutic concentration range for its therapeutic effects. In order to investigate this precisely, a study with a fixed-dose design is required.

The present study was therefore undertaken to examine the therapeutic spectrum of zotepine and its relationship with serum zotepine concen- trations.

SUBJECTS AND METHODS The subjects consisted of 21 in-patients (nine males, 12 females) fulfilling the criteria for schizophrenia according to DSM-III-R. They were further diag- nosed into four types of schizophrenia (eight cases, undifferentiated; eight, paranoid; three, disorga-

088%222/93/020 133-07$08.50 0 1993 by John Wiley & Sons, Ltd.

134 T. KONDO ET AL

nized; two, catatonic). All patients had total Brief Psychiatric Rating Scale (BPRS) scores (Bech et al., 1986) of 17 or more. They gave informed con- sent to participate in this study. The mean (range) age and duration of illness were 32 (1868) years and 82 (6-458) months, respectively. All patients were physically healthy, and none had received any medication at least for one month. Eleven patients were smokers (more than 10 cigarettedday).

Zotepine was administered twice daily (7 a.m. and 7 p.m.). The daily dose was 100 mg in the first week and then increased and fixed to 200mg/day for the following 3 weeks. The observation period was 4 weeks. Biperiden, which was already reported to have no influence on serum concentrations of the drug or psychotic symptoms during zotepine treatment (Otani et al., 1990), was co-administered to five patients with extrapyramidal side-effects. Other co-administered drugs were flunitrazepam (four patients) and sennoside (two patients). Assessment of clinical status by BPRS and blood sampling was undertaken before morning dose, before treatment and weekly during the treatment period. Serum concentrations of zotepine were measured in duplicate by gas chromatography (Noda et a)., 1979).

The BPRS item ‘disorientation’ was excluded from analyses since no patient showed clouded con- sciousness. The remaining 17 BPRS items were divided into three subgroups, i.e. positive, negative, and anxietydepression symptoms as shown in Figure 1. Weekly improvement after zotepine treat- ment was expressed by percentage improvement (YO improvement), which was calculated from weekly amelioration scoredpre-treatment score multiplied by 100. A responder was defined as a patient who

showed percentage improvement of 50 per cent or more after 4-week treatment.

Statistical analyses were performed by linear and quadratic regression, Spearman rank test, Wil- coxon rank-sum test, Friedman rank test, and Tukey test. A P value of 0.05 or less was regarded as statistically significant.

RESULTS Twenty of 21 patients completed our study sche- dule. One female patient (paranoid type, smoker), dropped out due to poor drug compliance. Thirteen out of 20 patients (65 per cent) responded to zote- pine treatment irrespective of gender, age, smoking, type of schizophrenia, or co-administration of flu- nitrazepam.

The percentage improvement (mean kSD) in total BPRS symptoms over 4 weeks in 20 patients was 63.4 f 25-5 per cent, and those for the three BPRS subscales were 64.4 f 30.7 per cent for posi- tive, 41.8 f 53.9 per cent for negative, and 74.2 f 28.1 per cent for anxiety-depression symptoms (Table 1). Figure 1 illustrates the values of percent- age improvement in 17 BPRS items in 20 patients. All of anxiety-depression symptoms were greatly reduced by zotepine treatment while zotepine was less effective in reducing negative symptoms. The values of percentage improvement varied consider- ably among positive symptoms.

Figure 2 shows the time courses of BPRS scores during zotepine treatment. The mean total BPRS scores were significantly reduced after 2 weeks (2-4 weeks,p < 0.001). Similarly, those with positive (2- 4 weeks, p < 0401) and negative symptoms (2 weeks, p < 0.01; 3-4 weeks, p < 0.001) were also

Table 1. Weekly percentage improvement during zotepine treatment in responders and nonresponders

1 week 2 weeks 3 weeks 4 weeks

Total R 48.2 f 21.2 71.5 f 15.0**

Positive R 45.7 f 26.6 74.1 f 26.7*

Negative R 40.2 f 46.3** 65.0 f 25.6**

NR 27.0 f 26.9 32.2 f 22.9

NR 27.3 f 44.5 32.0 f 32.8

NR - 17.8 f 38.9 -9.1 f 44.5 Anxiety- R 65.6 f 28.2 77.3 f 24.7 depression NR 42.5 f 32.4 72.3 f 20.3 R responders (n- 13), NR: nonresponders (n=7) The values in the table are expressed as mean i s.d. (%) Significantly different fromnonresponders (*p<O.OS, **p<O.Ol)

71.6 f 14.7** 39.0 f 21.0 80.3 f 19.5* 43.0 f 23.7 62.9 f 27.0*

60.2 f 28.9 52.3 f 38.7

-2.9 f 52.5

80.7 f 11.2** 31.2f 5.9 82.2 f 20.4** 31.3 f 15.6 71.7 f 22.9**

84.7 f 16.0 54.6 f 34.7

- 13.7 f 50.8

ZOTEPINE, THERAPEUTIC SPECTRUM AND SERUM CONCENTRATIONS 135

Positive I Psychomotor asi tation Specific motor disturbances Uncooperat ive nes s Conceptual disorganization Hostility Hallucinations Unusual thought content Susp i c i ou sne ss Exaggerated se 1 f-esteem

Negative Blunted affect Emotional withdrawal Psychmotor retardat ion

Am i e t y-dep re s s i on

Anxiety (scantic) Somatic concern Depressive mood Anxiety (psychic) Selfdepreciation

7 4 . 9 0. 2 0. 2 '. 7 . 2

93. 4. 2 9

I

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Figure 1. Percentage improvement in 17 BPRS items after 4-week treatment with zotepke in 20 schizophrenic patients

significantly decreased after 2 weeks. The mean scores in anxiety-depression symptoms were signifi- cantly reduced after 1 week (1 week, p < 0.01; 2 4 weeks,p < 0.001).

Weekly values of percentage improvement were compared between 13 responders and seven nonres- ponders as shown in Table 1. The values of percent- age improvement in total ( 2 4 weeks,p c 0.01) and positive symptoms (2-3 weeks, p < 0.05; 4 weeks, p < 0.01) differed significantly between these two groups after 2 weeks. Significant differences in the values of percentage improvement in negative symptoms were found between the two groups after 1 week (1-2 and 4 weeks, p < 0.01; 3 weeks, p c 0.05). However, the values of percentage improvement in anxiety-depression symptoms did not differ significantly between the two groups at any week.

Twelve of 13 responders showed more than 50 per cent reduction in total BPRS symptoms at 2 weeks while six of seven nonresponders showed less than 50 per cent reduction at 2 weeks (Figure 3).

Consequently, in 18 of 20 patients (90 per cent), the clinical response at 2 weeks corresponded well to the final outcome of 4-week treatment.

In the present subjects, no significant linear or therapeutic-window relationship was observed between the mean serum concentrations of zotepine (2-4 weeks) and the values of percentage improve- ment at 4 weeks in total BPRS or the three subscales (Figure 4). No significant correlation was found even among the 13 responders. There was no signi- ficant difference in the mean serum concentrations of zotepine between responders (43.2 f 42-7 nghl) and nonresponders (34.3 f 35.9 ng/d).

DISCUSSION The present study provides some useful infor- mation on the efficacy of zotepine although it should be stressed that this was an uncontrolled study. Zotepine has a broad therapeutic spectrum in the treatment of schizophrenia. It is particularly effective in reducing anxiety-depression symptoms

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even though such symptoms are not specific to schi- zophrenia. These effects appeared at 1 week, and persisted during 4-week treatment in both res- ponders and nonresponders. Therefore, zotepine has immediate and potent anxiolytic-antidepressive effects in the treatment of schizophrenia, confirm- ing the suggestion by Fleischhacker et al. (1989). The anxiolytic-antidepressive effects of this drug may be ascribable to its antiserotoninergic effects (Yamawaki, 1987) since there is increasing evidence suggesting that serotonin antagonism is related to anxiolytic and antidepressive effects of psychotro- pic drugs (Cowen, 199 1). Interestingly significant improvement in anxietydepression symptoms was observed even in the nonresponder group.

With respect to the degree of response and the onset of effects, the improvement in positive symp- toms was similar to the overall efficacy. However, amelioration in the hallucinatory and delusional symptoms were less prominent than those of the remaining positive symptoms. This might be partly

due to the fact that zotepine has weaker antidopa- minergic effects than standard antipsychotic drugs such as haloperidol (Yamawaki, 1987).

Barnas et al. (1992) showed the effectiveness of relatively low doses of zotepine (50-150 mglday) against negative symptoms in chronic schizo- phrenic patients. In the present study improvement in negative symptoms was less remarkable than the positive and anxiety-depression symptoms. In non- responders, negative symptoms were not amelior- ated, and sometimes were accentuated. However, consistent reductions in these symptoms were observed in responders (Table 1). It should also be stressed that zotepine slightly improved negative symptoms in responders although our study dif- fered from that of Barnas et al. (1992) in terms of study design and selection of subjects. For exam- ple, a larger dose (200 mg/day) was administered to schizophrenic patients in acute exacerbation of illness in our study. The present results thus suggest that zotepine may be useful for the treatment of

ZOTEPINE, THERAPEUTIC SPECTRUM AND SERUM CONCENTRATIONS 137

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Figure 3. Prediction of the outcome after 4week treatment with zotepine by percentage improvement in total BPRS scores at 2 weeks. Eighteen of 20 patients (90 per cent) are correctly predicted (closed circles)

negative symptoms in some patients. Like cloza- pine, zotepine may be effective on negative symp- toms because of its potent antiserotoninergic effects (Yamawaki, 1987).

In the present study, the clinical responses at 2 weeks were significantly different between res- ponders and nonresponders. Especially, the values of percentage improvement in positive and negative symptoms at 2 weeks differed clearly, and this tend- ency persisted until the end of the 4-week study. In addition, the percentage improvement in total BPRS symptoms at 2 weeks corresponded well to the final clinical response, suggesting that an assess- ment of clinical status at 2 weeks may be useful as a predictor of the final outcome.

For a reliable assessment of the relationship between plasma concentration of an antipsychotic drug and clinical effects, a fixed-dose study is

required since a flexible-dose strategy will, by design, alter and confound the relationship between plasma concentration and cliical efficacy (Davis et al., 1985). Among many antipsychotic drugs, chlorpromazine and haloperidol have been most intensively studied by the fixeddose design. However, a therapeutic concentration range of chlorpromazine has not been defined (Van Putten et al., 1981), and that of haloperidol is still a matter of debate (Van Putten ef al., 1992; Volavoka ef al., 1992). To our knowledge, the present study is the first fixeddose study on the relationship between serum concentrations of zotepine and the clinical efficacy. No definite relationship was found in this study although this negative finding might be partly due to the few data at high serum concen- trations (only one case exceeded a serum concen- tration of 60 ng/ml) and the inclusion of

I38 T. KONDO ET AL

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Figure 4. Relationship between mean serum zotepine concentrations (2-4 weeks) and percentage improvement (4 weeks) in total, positive, negative and anxiety-depression symptoms in 20 patients, showing no linear or therapeutic window type correlations

nonresponders to zotepine treatment in the ana- lyses. In addition, the possibility that zotepine has pharmacologically active metabolites cannot be entirely excluded although there is no evidence to support this at present. Nevertheless, the present study suggests that monitoring of serum concen- tration of zotepine itself is of little significance for the prediction of the clinical response to zotepine treatment.

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