Centbutindole vs trifluoperazine : a double-blind controlled clinical study in acute schizophrenia.DR Doongaji, RS Satoskar, AS Sheth, JS Apte, AB Desai, BR Shah
Twenty-nine acute schizophrenic patients were treated under double-blind conditions for six weeks with either centbutindole in a dose range of 3 mg/day to 4.5 mg/day or trifluoperazine in the dose range of 15 mg/day to 22.5 mg/day. Both drugs produced a significant improvement in initial psychopathology. No significant differences were demonstrated between the two treatment conditions.
Keywords: Adult, Clinical Trials, Comparative Study, Double-Blind Method, Female, Human, Male, Pyrazines, adverse effects,pharmacology,therapeutic use,Random Allocation, Schizophrenia, diagnosis,drug therapy,Support, Non-U.S. Gov′t, Trifluoperazine, adverse effects,pharmacology,therapeutic use,
Centbutindole is an indigenously synthesized neuroleptic agent structurally similar to haloperidol. Preclinical studies on centbutindole suggest that it possesses appreciable central dopamine receptor blocking properties. Our preliminary impression of this drug was that centbutindole appeared to resemble trifluoperazine rather than haloperidol in its spectrum of activity.
The present study was conducted with the objective of comparing the efficacy, clinical profile and safety of centbutindole with that of trifluoperazine in acute schizophrenic patients.
This study was conducted in the inpatient services of the Departments of Psychiatry and Clinical Pharmacology, K.E.M. Hospital and Seth G.S. Medical College, Bombay. Schizophrenic patients, between the ages 18 and 45 years and diagnosed according to the Research Diagnostic Criteria (RDC) were hospitalised for the study.
A detailed physical examination was performed on each patient and haematological and biochemical investigations were carried out. Patients suffering from a concurrent systemic illness and pregnant women were excluded from the study.
The patients were rated on the modified Brief Psychiatric Rating Scale (BPRS) initially at hospitalisation, and after one week of placebo treatment. Those patients who either totalled 35 points on the BPRS initially or whose total BPRS scores showed a reduction of 20% at the end of this one week period were excluded from the study.
Patients were randomly assigned to one of the two treatment groups using a double-blind design, viz., centbutindole in two equally divided doses of 3 mg/day, or trifluoperazine in two equally divided doses of 15 mg/day. This dose was maintained for the first three weeks. For the next three weeks, the dose of centbutindole was increased to 4.5 mg/day and that of trifluoperazine to 22.5 mg/day in those patients whose reduction in total BPRS scores at the end of 3 weeks was 50% as compared to baseline scores.
All patients were evaluated independently by two raters initially and at weekly intervals on the BPRS, the Extra-Pyramidal Rating Scale, the Side-Effect Symptom Check-list (SESC), and on the Clinical Global Impression Scale (CGIS) for the duration of the study.
One hundred and two patients were screened for possible inclusion in the study. Sixty-two patients (61%) were excluded from the study due to the following reasons:
(i) Failure to satisfy inclusion criteria after the pre-treatment placebo period (n = 39).
(ii) Refusal for hospitalisation (n= 11).
(iii) Absconding from the ward during pre-treatment placebo period (n = 6).
(iv) Concurrent systemic illness (n=5).
(v) Pregnancy (n=1).
The remaining forty patients were included in the study. Twenty-nine patients completed the study, fourteen under centbutindole treatment conditions and fifteen under trifluoperazine treatment conditions. Eleven patients dropped out of the study, six under centbutindole treatment conditions and five under trifluoperazine conditions.
[Table 1]shows the demographic characteristics of the patients. Both groups of patients were well-matched for age, sex, body-weight, number of previous episodes, family history, type of schizophrenia and duration of illness. Within group comparison showed a significant reduction in median total BPRS scores in both the treatment groups [Table 2].
A 50%, reduction in median total BPRS scores was seen under centbutindole treatment conditions while a 44% reduction was seen under trifluoperazine treatment conditions at the end of the study period. Between group comparison for initial median total BPRS scores revealed no significant differences, the two groups being evenly matched for initial psychopathology. A similar comparison of the final median total BPRS scores also revealed no significant differences between the two treatment groups, the two drugs being comparable in their overall clinical efficacy.
Within group comparison of the median scores of the individual BPRS variables showed a significant reduction in the median scores of fourteen of the twenty-four BPRS variables under centbutindole treatment conditions and in eleven BPRS variables under trifluoperazine treatment conditions. Between group comparison failed to reveal any significant differences between the two treatment groups. No significant reduction was seen in the median scores of the following nine variables in both the treatment groups viz. "guilt feelings", "mannerisms and posturing", "grandiosity", "depressive mood", . hostility", "unco-operativeness". "excitement", "elated mood" and "motor hyperactivity".
There was a significant reduction in the median scores of all the BPRS factors at the end of six weeks in both the treatment groups [Table 3].
Within group comparison of the median scores on the CGIS variable "severity of illness" showed a significant reduction in median scores in both the treatment groups at the end of the six weeks study period [Table 4]. An identical final median score of 1.5 was seen in both the treatment groups on the CGIS variable "Global Improvement", indicating that patients in both the treatment groups were rated as "very much improved" at the end of the study. On the third CGIS variable "efficacy index", a final median score of 1 .5 seen under centbutindole treatment conditions implied a "moderate therapeutic effect" in contrast to a "marked therapeutic effect" seen under trifluoperazine treatment conditions.
Between group comparison did not show any significant differences on any of the CGIS variables.
Extra-pyramidal reactions and autonomic nervous system side-effects were the commonest treatment emergent symptoms observed in both the treatment groups [Table 5]A greater number of extra-pyramidal reactions were seen under centbutindole treatment conditions. Between group comparisons for the incidence of treatment emergent symptoms did not show any significant differences.
[Table 6]shows the mean daily dose of trihexiphenidyl administered to the two treatment groups to control extra-pyramidal reactions. There were no significant between group differences in the dose of trihexiphenidyl administered during the study except during the third week of the study. This single isolated significant difference could be due to a chance occurrence.
All haematological and biochemical investigations were within normal limits in both the treatment groups at the end of the study.
An initial one week pre-treatment placebo period was included in the study to exclude milieu responders, spontaneous remitters and mild cases of schizophrenia in whom the magnitude of change on the rating scales would have been small. Thirty-nine patients (38%) out of the hundred and two patients screened for possible inclusion in the study were excluded for this reason. Comparison between centbutindole and trifluoperazine showed a significant improvement in initial psychopathology in both treatment groups as seen from the reduction in total BPRS scores. This improvement was evident from the end of the first week of the study, implying that the onset of action of both these drugs was evident after one week of treatment.
When the individual BPRS items were ranked according to the percentage reduction in median scores, the greatest reduction was seen in the scores of the following variables, viz., "suspiciousness", "hallucinatory behaviour" and "unusual thought content", in both the treatment groups.
A similar ranking of the median scores of the BPRS factors showed that the factor ranking was identical in both the treatment groups, viz., "hostility", "thought disturbance", "anxiety-depression" and "activation" in descending order. Thus, centbutindole appears to be an incisive antipsychotic agent similar to trifluoperazine rather than exhibiting sedatives antipsychotic properties.
A final median score of 1.5 on the "Global Improvement" variable of the CGIS indicated that patients in both treatment groups were rated as "very much improved" at the end of the study. However, when the "Efficacy Index"-i.e., ratio of therapeutic effects to side effects-was calculated for each treatment group, the median final "Efficacy Index" score was 1.5 under centbutindole treatment conditions and 2.00 under trifluoperazine treatment conditions. Thus, a "moderate therapeutic effect" was observed under centbutindole treatment conditions in contrast to a "marked therapeutic effect" seen under trifluoperazine treatment conditions. This difference, although not reaching significant levels, could possibly be due to a greater number of troublesome treatment emergent symptoms seen under centbutindole treatment conditions.
A greater number of treatment emergent extra-pyramidal reactions were observed in the group of Patients treated with centbutindole, and this group of patients was administered a higher mean daily dose of trihexiphenidyl to control extra-pyramidal reactions.
The results of this study indicate that centbutindole is an effective incisive neuroleptic drug, comparable in its clinical profile to trifluoperazine, when studied under double-blind conditions, though structurally related to haloperidol.
The authors thank the Dean, Seth G.S. Medical College and K.E.M. Hospital for permission to conduct and publish this study. Grateful acknowledgement is made to Chemosyn Pvt. Ltd., Bombay, for financial assistance and supply of drugs.