Single versus divided doses of sintamil in depressionDR Doongaji, A Sheth, JS Apte, MR Datt, VK Mundra
Department of Psychiatry, Seth G, S. Medical College and K.E.M. Hospital, Parel, Bombay-400 012, India
Fifty one out-patient depressives were treated with Sintamil for a 5 week trial period under double-blind conditions. Sintamil 75 mg/day was administered in a fixed dosage schedule either as a single daily dose (SDS) or in 3 divided doses (DDS). There were no significant differences between the two treatment modalities in so far as efficacy was concerned. The SDS regimen of drug administration was associated with a lesser incidence of side effects.
Initial pharmacokinetic studies of Sintamil (Ciba 2330 Go), a new tricyclic antidepressant belonging to the dibenzoxazepine group, have shown that there is no difference in the blood level saturation with reference to the drug and its active metabolites when administered either as a single nightly dose or in three divided daily doses.
This paper presents a double-blind clinical study of this compound administered as a single dose versus three divided doses.
The study was conducted in the outpatient services of the Department of Psychiatry, K.E.M. Hospital, Bombay.
Patients of both the sexes, ranging in age from 18 to 60 years and with a duration of illness from one month to two years, were included in the study. A diagnosis of depression was made independently by two clinicians in every instance. Every patient was initially evaluated on the Hamilton Psychiatric Rating Scale for Depression (HPRSD) and assessments were repeated on days 8, 15, 22, 29 and 36. Treatment emergent side effects were recorded concurrently.
General physical examination including measurement of body weight, pulse rate, respiratory rate and blood pressure was done on each occasion.
Patients were administered Sintamil in a fixed dosage schedule, either in three divided doses (DDS) or in a single daily dose (SDS). The DDS consisted of 25 mg. of the drug administered thrice daily, while the SDS consisted of 75 mg. of the drug administered at bed time. The clinician who rated patients on each occasion remained the same throughout the trial period of 5 weeks and double data was analysed. The Chi Square test of significance was used to detect differences between the two treatment conditions throughout the study.
Fifty one patients completed the five weeks trial. Twenty four patients were treated under SDS conditions while 27 patients were treated under DDS conditions [Table 1]. All except 2 patient: scored less than 20 points on the HPRSD at the time of initial evaluation. Both these patients with high initial scores were treated under DDS conditions. There were twice as many patients in the trial population whose duration of illness was less than six months as compared to those whose illness was more than six months. The patients with the longer duration of illness were also unevenly distributed in the sense that there were 10 patients with longer duration of illness under DDS conditions while there were 6 patients of this type under SDS conditions.[Table 1].
In 9 patients under SDS conditions and in 6 patients under DDS conditions the improvement could be described as "excellent" (i.e., the reduction in their initial total symptom scores was between 76% to 100%). There was a significant difference in favour of DDS conditions for patients who showed "good response" to the drug (i.e., reduction in the initial total symptom scores between 50% to 75% ). This difference failed to reach significance when both the above groups of patients were combined [Table 2]. No significant differences could be detected between the two groups of patients with reference to either diagnostic categories or severity of illness. The total individual symptom scores showed progressive reduction over a period of 5 weeks under both the treatment conditions. The onset of action of the drug seemed to be during the first week of medication under both regimes. The greatest reduction in scores was seen for the variable "insomnia". The scores for this variable dropped from an initial value of 64 to 16 at the end of trial under SDS conditions. while the scores dropped from 64 to 8 under DDS conditions. However this difference was not statistically significant. [Table 3].
A greater number of patients developed a larger number of side effects under DDS conditions as compared to SDS conditions. The side effects emerged during the first week of medication under both treatment conditions. They disappeared at the time of the fifth evaluation under SDS conditions and no side effects were present at the end of the trial period. Under DDS conditions there was an increase in side effects during the third and fourth week of the trial and some side effects persisted, right up to the end of the treatment period. The common side effects under SDS conditions were dryness of mouth and constipation. The common side effects under DDS conditions were giddiness, dryness of mouth and constipation. [Table 4] and [Table 5]. The side effects were mild and did not require reduction in dose or addition of any adjuvant medication. No patient had to be discontinued from the trial because of them.
Seven patients under SDS conditions and 2 patients under DDS conditions did not complete the trial. All except one patient discontinued from the trial because they were not able to attend regularly. The remaining patient dropped out because there was no improvement in his base line symptom (Erectile dysfunction).
Analysis of the demographic data showed that the patient distribution was uneven in the two treatment groups. Thus more patients with greater initial pathology and longer duration of illness were treated under DDS conditions as compared to SDS conditions, although this difference was not significant and the total number of patients treated was also small. [Table 1]. Inspite of this there was a significant reduction in the initial total symptom scores in favour of DDS conditions as the scores dropped from 390 to 100 [Table 3]. The greatest reduction in scores was seen for the variable insomnia on HPRSD [Table 3]. Here there was greater reduction in scores under DDS conditions as compared to SDS conditions. However this difference was also not statistically significant. Except for these two observations there seemed to be no difference between DDS conditions and SDS conditions, in so far as therapeutic efficacy was concerned.
There seemed to be an obvious difference when treatment emergent symptoms were compared under the two regimes. The number of side effects was larger under DDS conditions and they were also reported by a greater number of patients [Table 4]. At the end of the trial period no side effects were reported under SDS conditions, while side effects persisted right up to the end of the treatment period under DDS conditions [Table 5]. Thus the SDS regimen of drug administration seemed to be better than the DDS regimen, in so far as patient's acceptability and emergence of side effects were concerned.
The findings reported in this study are different from those reported in another similar study by Mahendru and Shukla.  Apart from the obvious differences in sex distribution of the patients on trial, and differences in duration and severity of illness, an important distinction between the two studies was that the present study was carried out on both neurotic and psychotic varieties of depression. Neurotic depressions were included in the trial as the preclinical pharmacological data and the results of previous clinical studies indicated that Sintamil was effective in controlling anxiety, agitation, and insomnia in addition to depressive symptoms.  Further evidence in support of this observation is the fact that concomitant medication with tranquillizers was not found necessary in this study in spite of the fact that there was a large number of patients with symptoms of anxiety and insomnia on trial. It is also pertinent that the greatest reduction in the initial symptom scores was found for the variable insomnia under both the treatment regimes as pointed out earlier.
Finally, there is no evidence from Mahendru's study  to suggest that there was a lesser incidence of side effects under SDS conditions as compared to DDS conditions as reported here.
The authors thank Dr. C. K. Deshpande, Dean, Seth G. S. Medical College and K.E.M. Hospital, Bombay-400 012 for the permission to conduct and publish this research and CIBA (India) Ltd. for the supply of drug.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]