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A double blind trial of piracetam (UCB 6215) and placebo in cases of post-ECT cognitive deficiency.
Psychiatry and neurology have, till today, nothing to offer to patients suffering from cognitive deficit. Though an attempt can be made to remove the underlying cause, the damage already done to the brain can rarely be undone. A new drug, Piracetam (UCB 6215) is claimed to have activation, protection, and function restoring effects on nerve cells in distress. Piracetam, 2-pyrrolidone - acetamide has the following chemical structure [Fig. 1]. Experimentally, it has been reported that piracetam exerts a protection effect against audiogenic epileptic seizures in rats and the disturbing effects of ECT, senescence, alcohol intoxication and hypoxia upon learning in mice and rabbits. Further, it facilitates the learning and the memory fixation in rats.[6] No serious toxicity was observed in previously reported evaluation in humans.[4] It is postulated that these effects on central nervous system are exerted directly on the cerebral cortex. The drug possesses no sedative or stimulatory effects, and does not influence behaviour; in this respect, it differs from the psychotropic agents. This investigation was undertaken to study the effect of piracetam in postelectro-convulsive treatment (ECT) cognitive deficiency in a double blind study.
Patients attending the out-patient department of K.E.M. Hospital, Bombay, and diagnosed as having 'depression' by two consultant psychiatrists, independently and requiring ECT as one of the treatments, were considered for the trial. The patients were examined specifically for evidences of cognitive deficiency. Also psychometric investigations were done to detect the cognitive deficiency. These investigations were. 1. Wechsler Memory Scale: It consists of seven subtests, viz. (i) Personal and current information, (ii) Orientation, (iii) Mental control, (iv) Logical memory (immediate recall), (v) Memory Span (digits forward and backward), (vi) Visual reproduction, (vii) Associative learning. Purpose: It tests memory. 2. Kohs block test: It consists of sixteen coloured inch cubes. All the cubes have their faces painted in the same way-white, yellow blue, and red, red and white divided diagonally and yellow and blue divided diagnoally. There are ten designs painted in the same colours, red, yellow blue and white on card board oblong 3" by 4". Purpose: This test measures analyticosynthetic ability. 3. Passalong test: This test consists of four boxes of different sizes, eight blocks of one size, two red and six blue; three blocks of larger size, one red and two blue; and two large square blocks; one red and one blue; a set of eight coloured diagrams showing the final positions for each of the eight sub-tests. Purpose: It measures intelligence (through specific factor). Only those patients who did not have cognitive deficiency to start with on clinical and psychometric examination, were considered for the trial. The patients were given 6 ECTs on alternate days. No active drug was given concurrently. Sinusoidal alternating current of 100 volts for a period 1.0 sec. was used to produce convulsions. At the end of 6 ECTs patients were again examined clinically and tested psychometrically as mentioned above for detection of cognitive deficiency. If the patient developed post-ECT cognitive deficiency, then only the patient was included in the trial. The patient on developing post-ECT cognitive deficiency was categorised clinically into mild, moderate and severe on the following basis. The patient was put in mild category when patient himself did not complain of forgetfullness but relatives complained that patient was forgetful and/or patient had forgetfullness of incidents 24 hours back. The moderate category included those patients who had forgetfullness of incidents three hours back, and severe category included patients who had confusion. The patients were given randomly either piracetam (UCB 6215) or placebo in a double blind way. The preparations used (piracetam and placebo) were identical in appearance. Neither the patient nor the physician knew who was being given piracetam and who the placebo. The dose consisted of two capsules of 400 mg each three times a day i.e. 2.4 gm/day or two capsules of placebo three times a day. The drug was administered for six weeks or till complete recovery was there, whichever was earlier. No active drug was given concurrently except chloral hydrate 30 ml. at bed time as a hypnotic, whenever indicated. Once in the trial, patients were examined clinically and tested psychometrically as mentioned above every week till there was complete recovery. The results were tabulated. At the end of the study decoding was done and Chi square test was used to find out statistical significance at 5% level. Initially 134 patients were considered for the trial. Out of these 134, 43 patients completed 6 ECTs. Twenty seven patients i.e. 62.8% developed post-ECT cognitive deficiency. These patients were then included in the trial. Three patients dropped out. Hence data of 24 patients was available for the analysis.. The patients ranged from 20 years to above 60 years in age, and were found to be evenly distributed. Diagnostic evaluation is shown in [Table 1].
These are presented in [Table 2]. It can be seen from the table that there were 13 patients on piracetam and 11 patients on placebo. In the case of patients who were on piracetam, there was no case in category of mild cognitive deficiency, there were 10 cases in moderate category, 8 of whom recovered at the end of two weeks and remaining 2 cases at the end of three weeks. All the three cases of severe category recovered at the end of 4 weeks. In the case of patients who were on placebo there were 3 cases in the category of mild cognitive deficiency, two of whom recovered at the end of one week and remaining one at the end of two weeks. There were 8 cases in moderate category; four recovered at the end of two weeks and remaining four recovered at the end of three weeks, There was no case in the severe category. All the cases had complete recovery by the end of four weeks whether on piracetam or on placebo. No side effects were noted. When this data was subjected to statistical analysis, no significant difference was noticed between the drug and the placebo on the recovery rate from the cognitive deficiency produced by ECT. However, if one considers only the patients suffering from moderate cognitive deficiency, it will be noted that 80% of the patients on piracetam recovered within 2 weeks whereas only 50% of those on placebo recovered in the same period, suggesting that the drug may be superior to placebo. This observation needs to be confirmed by further work. Psychometric evaluation According to the psychometric evaluation, the results are shown in [Table 3]. These findings also confirmed the clinical observations that there was no significant difference between the drug and the placebo.
The evaluation of drugs such as piracetam is beset with inherent difficulties. No two patients suffering from organic brain syndrome are alike; therefore, it is very difficult to get a matching control population. Similarly, the rate of natural improvement, remission, or deterioration cannot be predicted even in cerebrovascular accidents, much less in the senile dementias. The testing for cognitive deficit is also fraught with dangers as the tests have to be simple enough for the patient to understand, but sensitive enough to pick up the cognitive deficit. ECT is known to produce cognitive deficiency similar to what is observed in organic brain syndrome. About 60% of the patients undergoing treatment with ECT develop cognitive deficiency, ranging in intensity from mild to very severe. This deficiency is usually influenced by the strength of the current, the number of stimuli, the frequency of treatment, the technique-whether bilateral or unilateral, and the condition of the brain which is subjected to this treatment. Patients usually recover from this deficiency in about 3 to 6 weeks unless its intensity is very severe in which case it might take upto a maximum of 6 months for total recovery. Till to-day there is no conclusive evidence that ECT produces any permanent damage in a healthy fully developed brain. Various workers have studied the effect of piracetam on organic brain syndromes and have claimed favourable results.[1],[2],[3],[4],[5],[6],[7] Our study shows that piracetam is not better than placebo in the recovery from cognitive deficiency.
We wish to thank the Dean, Seth G.S. Medical College and K.E.M. Hospital for permission to carry out the study and for the use of hospital records. We thank M/s Unichem Laboratories for the supply of drugs and financial assistance.
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