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ZOTEPINE VS. HALOPERIDOL IN ACUTE SCHIZOPHRENIA: A DOUBLE BLIND TRIAL

Ch. H. Stuppack, Ch. Barnas, B. Unterweger, C. Miller, W.W. Fleisch- hacker and H. Hinterhuber

Department of Psychiatry, Innsbruck University Clinics, Anichstrasse 35, A-6020 Innsbruck, Austria

Zotepine is a dibenzothiepin derivate closely resembling clozapine and fluperlapine (1) - The pharmacological profile is comparable to substances such as thioridazin and chlorpromazine (2). Its potential to accelerate dopamine turnover is bigger than that of chlorpromazine and lower than that of haloperidol.

Thirty-four patients suffering from acute paranoid schizophrenia fulfilling DSM III criteria were randomly allocated to two groups receiving their haloperidol (lo-30 mg, mean 18.6) or zotepine (200- 600, mean 387 mg). Patients were to be evaluated for six weeks. To quantify psychopathology CGI and BPRS were used. Vital parameters, CBC, blood chemistry, ECGs and EEGs, were monitored regularly.

Seven of the 18 patients in the zotepine group dropped out for the following reasons: one showed marked extrapyramidal side effects, one developed an increase of liver transaminases (GOT 104, GPT 272, gamma GT 981, five patients showed no positive response to the drug, they did not complete the whole 6-week trial. From the 16 patients receiving haloperidol, one refused to take the drug after three weeks, two patients dropped out due to organizational problems and one showed severe extrapyramidal side effects. Medication was stopped in four patients because of non-response. If one drops patients failing to complete the trial due to organizational reasons or side effects, from an improvement analysis nine patients in the zotepine group showed marked or moderate improvement (CGI) as opposed to seven patients who showed no or only slight improvement. The respective numbers for haloperidol are seven patients with marked or moderate improvement vs. five with no or slight improvement.

BPRS baseline was 69.9 for both groups. Scores decreased to 42.1 (zotepine) and 31.4 (haloperidol) on day 28. There was no significant difference between groups concerning CGI and BPRS scores. The improvement in both groups was statistically significant on all rating points until day 28, after which no statistical analysis was carried out due to decreasing sample size.

Results of BPRS subscores did not show any significant differences. Only a trend in favor of zotepine could be noticed in the factor 'anxiety and depressive mood'. Haloperidol seemed to have a stronger influence on 'thought disturbances' and 'activation'.

The following side effects were registered: rigor and tremor were seen much more often in the haloperidol group, akathesia, orthostatic hypotension and sedation were evenly distributed in both groups. A transient increase of liver transaminases developed in 11 patients treated with zotepine and in five patients in the haloperidol group. No ECG effects were noticed. The EEGs of two zotepine and one haloperidol patients showed very slight alterations at baseline which had subsided by the time of control EEGs.

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The study presented shows rapid onset of antipsychotic action of both drugs. No differences in this regard could be demonstrated by statistical evaluation in the dose range used. The fact that zotepine seems to have positive effects on anxiety and mood has already led to atria1 in major depression and also reflects our experience with the drug against negative symptoms in schizophrenia (3). It is remarkable that zotepine patients suffered from less extrapyramidal side effects. This fact could be expected because of the structural relationship to clozapine. Previous experiences seem to suggest that the liver transaminases increase might be a dose dependent effect with a higher incidence in doses over 300 mg/day.

1. Zotepine (Expose-2nd ed). Ed: Fujisawa Pharmaceutical Co., Ltd., Osaka 1982

2. Uchida, S. et al. Pharmacological study of (2-chloro-11-(2- dimethyl-aminoethoxy)dibenzo(b,F)thiepine) (Zotepine), a new neuroleptic drug. Arzneim. Forsch/Druas Res. 29:1588-1594, 1979

3. Fleischhacker, W. et al. Results of an open phase 11 study with zotepine - a new neuroleptic compound. Pharmacopsychiat. 20:58-60, 1987

THE NARROW THERAPEUTIC INDEX OF HPL: A DOSE COMPARISON STUDY

Theodore Van Putten, M.D.

UCLA School of Medicine, Veterans Administration Medical Center, Los Angeles, CA 90073, USA

Seventy-two newly (rejadmitted drug-free schizophrenic (by DSM III) men were randomly assigned to receive haloperidol (HPL) either 5, 10 or 20 mg daily for four weeks. In case of non-response, the doctor could increase (or decrease) the dose for another four weeks accord- ing to his clinical judgment. Clinical response was measured at baseline, weekly for the first four weeks, and at week 8 after the flexible dose period.

After seven days of treatment, patients assigned to the 5 mg dose were not doing as well as those assigned to the 10 and 20 mg doses. Specifically, they were less improved on the doctor's Global Improve- ment Ratings (p=O.O04); BPRS-Schizophrenia factor (p=O.O05); and BPRS-total (p=O.36). By the 14th day of treatment, patients on the 5 mg dose had nearly caught up with the others in terms of antip- sychotic effects. However, by the second week, patients on the 20 mg dose actually became worse on BPRS-Withdrawal Retardation (-31%; P = 0.007) and were experiencing considerably more akinesia (p = 0.00001). By the third and fourth weeks of treatment, all groups were doing equally well in terms of antipsychotic effect, but the patients on the 20 mg dose continued to deteriorate on BPRS-Withdrawal- Retardation and akinesia ratings. Patients assigned to the 20 mg dose left hospital against advice significantly more often (35% vs. 4% for the 5 and 10 mg group combined; p=O.O06). A 20 mg daily dose of HPL, therefore, has substantial neurotoxic effects by the second week of treatment.