A preliminary study of etafenoxineDR Doongaji, AS Sheth, JS Apte, MPE Bharucha, SP Ramesh, KN Padamsee, VN Vahia
Department of Psychiatry, Seth G. S. Medical College and K.E.M. Hospital, Parel, Bombay 400 012, India
Etafenoxine (Hoe 36 801), a new psychotropic compound was administered in a single blind study to 16 neurotic outpatients and 15 schizophrenic inpatients for a period of 4 weeks followed by a 2 week period of placebo administration. Improvement was reported for the psychic and somatic symptoms of anxiety accompanied by depression. The improvement observed in psychotic symptoms was minimal. Negligible side effects were noted in 6 patients.
Ever since the discovery of the use of chlorpromazine for the treatment of psychiatric illnesses, newer psychotropic agents are constantly being synthesised from the point of view of achieving greater therapeutic efficacy with lesser toxicity. There is a feeling in certain quarters that instead of studying the effects of a new compound on the course of a psychiatric illness, it may be preferable to study its action on certain target symptoms.
Etafenoxine (Hoe 36 801) is a new psychotropic compound which is chemically 6-chloro-4-methyl-4-phenyl-2-ethylamine-4H-3, 1-benzoxazine. The structural formula of the compound is as shown below:
In a number of animal studies it was shown to possess predominantly sedative activity. Early clinical reports suggested that it was effective in relieving certain target symptoms viz. psychomotor retardation, anxious or depressed mood, hypochondriasis, loss of appetite, fatigue, drowsiness, feelings of guilt, helplessness and hopelessness (Data supplied by the manufacturer).
It was thus considered worthwhile to study the effects of etafenoxine in neurotic and psychotic patients with reference to the above symptoms.
This trial was conducted on the psychiatric services of the K. E. M. Hospital, Bombay. The study population consisted of 16 outpatients who had psychoneuroses and 15 in patients who were diagnosed as schizophrenics. Their age and sex distribution and the duration of the illness are shown in [Table 1]. Patients were selected for the study if they showed one or more of the following target symptoms: decreased psychomotor activity, fatigue, general physical exhaustion, loss of interest, apathy and trouble in concentrating.
The following types of patients were excluded from this study:
1. Patients displaying acute anxiety, acute agitation and hallucinations.
2. Patients with history of epilepsy or glaucoma.
3. Patients suffering from gastrointestinal, hepatic, renal and cardiac dysfunction.
4. Women of child bearing age.
After an initial washout period of 3-7 days, there was a test drug trial period of four weeks. A fixed flexible dosage schedule was followed. The neurotic patients received etafenoxine in doses of 100 mg, daily, in two divided doses during the first week, 150 mg daily in the second week and 200 mg daily in the third and fourth weeks. The psychotic patients received 200 mg daily throughout the trial, Doses of more than 100 and daily were given in t.i.d. regimen.
In both the groups the active drug administration period was followed by a period of two weeks of placebo administration. The dose was increased or decreased depending on the therapeutic response and the treamtent emergent symptoms. However, no patient received more than 200 mg daily.
The neurotic outpatients were evaluated initially and at weekly intervals for a period of six weeks by two independent raters on the Clinical Global Improvement Scale (CGI), Hamilton's Rating Scale for Anxiety (HARS) (Hamilton, 1959) and Hamilton's Psychiatric Rating Scale for Depression (HPRSD) (Hamilton, 1960; Hamilton, 1967).
The psychotic inpatients were evaluated by two independent raters initially and again on 3rd, 7th, 10th and 14th days, and weekly thereafter for a total period of six weeks. The change was recorded on each occasion on the Clinical Global Improvement Scale ((CGI) and Brief Psychiatric Rating Scale (BPRS).
To assess the effect of etafenoxine on the organ functions, laboratory investigations such as Hb, WBC (total and differential), platelets, fasting blood sugar, alkaline phosphatase, bilirubin, SGOT, SG PT, blood urea and urine analysis were done initially and at the end of the treatment.
The correlation coefficient between the initial ratings of the two raters was found to be highly significant, therefore, the mean scores of the two raters have been subjected to analysis. Wilcoxon's signed ranks test (Siegal, 1956) has been employed to test the significance of differences for the entire data.
[Table 2] shows the analysis of the CGI in the 15 neurotic outpatients who completed the trial. Moderate to marked improvement was noted in 33% of the patients at the end of two weeks. Maximum improvement was noted at 4 weeks (46.7%) which was maintained till the end of the trial at 6 weeks, the last two weeks being the placebo period.
Analysis of the total scores of the HARS at weekly intervals showed significant overall improvement at all rating periods [Table 3].
Analysis of the individual variables of the HARS showed significant improvement in variables "anxious mood, tension, insomnia, depressed mood, intellectual functioning, general somatic symptoms, cardiovascular and gastrointestinal symptoms, and behaviour at interviews" at the fourth week evaluation. The same level of improvement was also maintained during the last two weeks of the placebo period for all except one of the variables viz. "cardiovascular symptoms".
Factor analysis of HARS scores showed significant improvement for both symptom groups 'viz. "psychic anxiety" and "somatic anxiety" at the end of 4 weeks, the improvement being maintained throughout the placebo period. However, the drug appeared to have somewhat greater effect on symptoms of psychic anxiety than on somatic anxiety [Table 4].
The results of the analysis of total scores of HPRSD showed that significant improvement occurred at all rating periods during the first four weeks and continued throughout the placebo period [Table 3].
On individual item analysis of HPRSD the variables "depressed mood, early and middle night insomnia, somatic anxiety, worthlessness, psychic anxiety, somatic symptoms related to gastrointestinal tract, hypochondriasis and helplessness" showed significant improvement at the end of the fourth week. This improvement was maintained throughout the placebo period.
[Table 2] shows the results of analysis of the total CGI scores of the 15 inpatients diagnosed as schizophrenics who completed the trial. Moderate to marked improvement was noted in 26.7% of the patients at the end of 4th week which was maintained throughout the trial including the two week period of placebo administration.
Analysis of the total scores of the BPRS showed significant improvement at all rating periods except at the end of the first week of the placebo administration (day 35) [Table 3].
The analysis of individual variables of the BPRS showed significant changes at 4 weeks for the variables "emotional withdrawal, somatic concern, hostility and blunted effect". This improvement was maintained for all these variables at the end of 6 weeks, the last two weeks being the placebo period.
Factor analysis of the BPRS scores (Guy and Bonato, 1970) showed significant improvement, for the symptom group `withdrawal retardation' at the end of four weeks [Table 5].
Drowsiness, giddiness and palpitations were the common side effects. These were noted in 5 patients with neurosis. Drowsiness was also reported by one schizophrenic patient. The side effects were noted in the early part of the trial and they lasted for about two weeks. In no instance were they sufficiently serious to exclude any patient from the study.
All the laboratory investigations were within normal range at the end of treatment.
Five neurotic patients dropped out from the outpatient study. Two of them failed to report after the first week of drug administration, while 3 patients dropped out during the second week of drug administration. No follow-up is available as these patients were not traceable.
Four inpatients with schizophrenia did not complete the trial. One patient was discontinued during the washout period as he was unable to continue as an inpatient. Another patient absconded on the tenth day of trial and could only be traced after about, a month. The third patient was detected to have developed signs of organic brain syndrome (extensor plantar responses and akinetic mutism) on the third day of admission. The last patient had to be discontinued during the 5th week of the trial (placebo period) as his mental status deteriorated as seen by marked restlessness, anxiety, insomnia and appearance of hallucinations.
The basis for selection of patients in this study depended upon the presence of one or more target symptoms which were thought to respond to the drug; Patients displaying hallucinations, acute anxiety and agitation were excluded. Consequently a potential source of error could have been introduced in the experimental design in so far as limitations were imposed for generating valid information about interactions between the responding and non-responding variables.
The drug seems to have a relatively early onset of action. The improvement was noted as early as the third day of treatment in some psychotic patients. This improvement continued even after cessation of active drug therapy and could be seen well within the placebo period at the end of the trial.
In the neurotic patients also the onset of drug action seemed to be in the first week of administration. The carry over of improvement into the placebo period was noted here too.
Etafenoxine effectively relieved the psychic and somatic symptoms of anxiety accompanied by depression. At this point in time it is not possible to state whether this could be a genuine drug effect which was carried over during the placebo period due to disruption of the underlying vicious neurotic cycle, or whether it was a placebo effect per se. At any rate the observation certainly deserves a second look and it may be worthwhile conducting another elaborate study using a more sophisticated design in neuroses accompanied by depressive symptoms.
A small but significant reduction in total BPRS scores occurred at all rating periods (except day 35) in the psychotic population. However, the overall impact of the drug on schizophrenics was minimal. Carry over of improvement in the placebo period does not permit one to exclude the contribution of the combined effects of placebo and milieu.
This study presents a case in point fox conducting a psychotropic drug trial utilising a cross over design with the patient acting as his own control during the period of placebo administration to counteract non-drug effects.
The authors thank Dr. C. K. Deshpande, Dean, K. E. M. Hospital and G. S. Medical College, and President, K. E. M. Hospital and Seth G. S. Medical College Research Society, Bombay, for permission to conduct and publish this study. Grateful acknowledgement is made to Hoechst Pharmaceuticals Limited, particularly to Dr. N. L. Chabria and Mr. V. A. Deshpande, for their valuable and personal assistance and cooperation[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]