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Does lofepramine have fewer side effects than amitriptyline?
355
Journal of Affective Disorders, 4 (1982) 355-363 Elsevier Biomedical Press
Does Lofepramine
have Fewer Side Effects than Ami trip tyline?
Results
of a Comparatrve
Trial
R. Pugh, Janne Bell, A.J. Cooper, S. Dunstan, D. Greedharry, P. Raptopoulos, Charmian Rowsell, J. Steinert and R.G.
J. Pomeroy, Priest *
Academic Deportment ofPsychiatry,St. Maty’s Hospital, Harrow Road, London W9 3RL. and St. Bernard’s Hospital, Uxbridge Road, Southall, Middlesex UBI 3ElJ (Great Britain) (Received 3 September, 1981) (Revised, received 5 April, 1982) (Accepted 21 April, 1982)
Summary A double blind trial was carried out comparing the tricyclic antidepressant lofepramine with amitriptyline in the treatment of patients suffering from moderate to markedly severe depression. No difference was demonstrated between the two drugs in terms of their antidepressant effect, but patients treated with lofepramine suffered from singificantly less side effects than patients treated with amitriptyline. Both groups of patients had a high drop out rate but this was less marked in the groups of patients treated with lofepramine.
Introduction The efficacy of the tricyclic antidepressant drugs may now be regarded as axiomatic. Particularly striking are the experiments which demonstrate an increased rate of reIapse when placebo is blindly substituted for the active preparation.
* Reprint Britain.
requests
to Professor
0 165-0327/82/0000-0000/$02.75
R.G. Priest, St. Mary’s Hospital,
D I982 Elsevier Biomedical
Harrow
Press
Road, London
W9 3RL, Great
356
Tricyclic antidepressants are widely used in medicine, and in the usual dosage the majority have proved to be relatively free from toxic effects, at least in short-term use. There is now a growing choice of such drugs available (Priest and Woolfson 1978) and it is necessary to evaluate the relative merits of each. Each drug or group of drugs, as it is introduced, must be compared against those previously in use, not only from the point of view of efficacy but also with regard to unpleasant side effects. There is ample reason, therefore, for adopting the comparative trial as a standard procedure. Amitriptyline is now the most commonly prescribed antidepressant in the United Kingdom, and in this study it has been adopted as the reference compound against which to assess the newer preparation lofepramine. Lofepramine is a dibenzapin derivative that differs from imipramine by the substitution of the aliphatic amino group by a 4’-chlorphenacyl group. It has a low toxicity in rats and mice compared with imipramine, desmethylimipramine, amitriptyline, maprotiline, and nomifensine, and the chemistry and pharmacology were first described by Eriksoo and Rohte (1970). Clinical trials elsewhere have suggested that in humans the antidepressant qualities are of acceptable magnitude but that it is less liable to cause adverse reactions (Obermair and Wegener 1978). In England McClelland and his colleagues (1979) have compared lofepramine with amitriptyline, using 35 mg and 25 mg tablets, respectively. They were unable to show a significant difference in their total sample, but noted that those patients with endogenous depression did better on lofepramine. Since it appears that lofepramine is at least as effective as amitriptyline the dosage described we adopted this regime in order to repeat the comparison of efficacy but also to see particularly whether there were conspicuous clinical differences in the amount of side effects produced by these two drugs. Method and Material Selection of subjects A consecutive series of patients was assigned to the trial. The patients comprised all those that arose in the clinical practice of one of us (J.S.) that were diagnosed as suffering from depressive illness and considered for tricyclic antidepressant medication, provided that certain criteria were met: (1) Age 15-75; (2) Either sex; (3) Not pregnant; (4) Not currently under treatment with other psychotropic drugs (except benzodiazepines or small doses of phenothiazines); (5) Depressive symptoms which would normally be treated with drugs by the clinician concerned. Patients were asked to take part in a clinical trial and informed consent was obtained. They took 2 tablets three times daily after meals (i.e. 2 X 35 mg tablets of lofepramine or 2 X 25 mg tablets of amitriptyline, 3 times daily). They were advised that, should side effects prove troublesome, they should omit the medication for 24 hours and then resume it at approximately half the previous level.
357
Assessment Progress was assessed by use of: (1) A global clinical rating scale; (2) Standardised psychological tests. These included the self rating depression scale developed by Zung (Zung 1965; Priest and Netter 1975). This complements the observer rating scale above by being free from observer bias. Assessment was carried out: (a) At the beginning of the trial (when weight and height were measured, and demographic data collected); (b) After 7-10 days; (c) After 4-6 weeks. Side effects Patients were told about possible side effects at the beginning of the trial. At that stage they were rated on pre-existing constipation, dry mouth, etc. to avoid these being mistakenly attributed to the drug (when in fact they are common symptoms of depressive illness). On subsequent occasions they were asked an open-ended question on symptoms that they had interpreted as side effects. They were then rated on a predetermined list of effects that are anticipated in a proportion of subjects taking tricyclic preparations (specifically dry mouth, blurred vision, drowsiness and constipation). For each putative side effect ratings were made (c.f. Priest 1976a) on: (a) relevance, (b) persistence, and (c) intensity, and an integrated index of severity was calculated. Each suspected side effect was rated according to severity (1 = mild, 2 = moderate, 3 = severe, 4 = very severe), frequency (1 = once, 2 = infrequently, 3 = often, 4 = continually) and the relationship that it seemed to bear to the administration of the drug (0 = not related, 1 = possibly related, 2 = definitely related). The index was calculated by multiplying together the scores on a, b and c above for each side effect. This is a slightly modified version of the previously used method (Priest 1976a), the main difference being that since the ‘not related’ category is coded as zero, the effect is to exclude this item from counting as a side effect. The logic of the remaining argument is that relevance, persistence and intensity all have a mutual effect that is best displayed as a product, rather than as a sum, of their individual degrees.
Results (I) General description of patients Altogether 56 patients were taken into the trial, 27 on lofepramine and 29 on amitriptyline. There were 30 drop outs of which 13 were on lofepramine and 17 were on amitriptyline. This difference is not significant (x2 = 0.62, P = 0.11). The age range was from 18 to 68, 15 patients were male and 41 female. There was no significant difference between patients allocated to lofepramine and
358
amitriptyline at the beginning of the trial in age, sex, previous psychiatric history and family history of psychiatric illness. Since depression covers such a wide spectrum it is of importance to other workers to have some idea of the level of severity of the patients in our trial. Before starting treatment the mean score on the Zung Self Rating Depression Scale (ZSDS) Index was 62.75. (2) Lofepramine Zung The ference or after
compared with amitriptyline
Self Rating Depression Scale results from this questionnaire are shown on Table 1. No significant could be shown between the two groups prior to treatment, after 7-10 4-6 weeks.
difdays
Psychiatrists global rating scale The results obtained using this scale are shown on Table2. No significant difference could be shown between the two groups. Thus no significant difference in outcome could be detected either by the psychiatrist global rating scale or by the ZSDS between patients treated with lofepramine and patients treated with amitriptyline. However, there was a difference in the drop out rate on the two drugs. At the 7-10 day assessment, of the 27 allocated to lofepramine 7 had stopped treatment, 3 were continuing at a reduced dose and 17 were continuing at full dose. The equivalent figures for amitriptyline were 9, 9 and 11 (total = 29). At the 4-6 week assessment, of those allocated to lofepramine 13 had stopped treatment, 3 were on a reduced dose and 11 were continuing at full dose. For amitriptyline the figures were 17, 5 and 7, respectively. There is clearly a trend in favour of lofepramine patients perservering more with their medication, but statistical significance is achieved only at the 7-10 day assessment (tau = 0.18, P < 0.05). TABLE
1
ZUNG
SELF RATING
DEPRESSION
SCALE
High score = severe depression. Mean scores
Score prior to treatment Score at 7-10 days Score at 4-6 weeks
Student’s
Lofepramine
Amitriptyline
I
P
61.62 63.17 56.20
63.89 64.63 59.31
0.51 0.36 0.71
0.6 1 0.72 0.48
0.28 0.25
0.778 0.805
Difference between scores prior to treatment Score at 7- 10 days 0.333 Score at 4-6 weeks 3.928
and the 1.937 5.08
359
TABLE
2
PSYCHIATRIST
GLOBAL
RATING
SCALE
High score = less severe. Mean scores
Score prior to treatment Score at 7- 10 days Score at 4-6 weeks
Student’s
Lofepramine
Amitriptyline
t
P
2.78 3.71 3.61
2.75 3.13 3.00
0.11
0.91 0.31 0.23
1.04 1.24
(3) Side effects In constrast to the lack of significant difference in therapeutic effect, a number of important differences in the incidence of side effects was found. We took two precautions before accepting them as valid. Firstly we subtracted the pre-trial scores obtained on such complaints as dry mouth and constipation. Secondly we used non-parametric statistics to infer probability values. Subtraction of the initial scores is now a recognised practice, and takes into account symptoms of the presenting depressive illness, including the high prevalence of dry mouth, constipation and other potential side effects. The need for non-parametric statistics arises from the nature of the data (Siegel 1956). The side effect ratings (and the differences derived from them by subtraction) cannot be considered as equal interval scales (in contrast to age, in which someone of 60 years may be justifiably regarded as twice as old as someone of 30 years). The ratings may be regarded, however, as representing the ordinal level of measurement. For instance, with a rating scale which goes from 1 (mild) to 4 (severe) one may assume that a person in category 4 is worse than one in category 2, but not necessarily twice as badly off. We have used Kendall’s tau as the statistic for dealing with this data. The case for using this with survey data has been argued before (Priest 1971, 1976b). Kendall’s tau is a rank order correlation coefficient that makes no assumptions about the distribution of the data (other than that they can be seen as categories ranked in order), and it does not pay undue attention to outlying values. We favoured tau (c) as recommended for oblong tables (Kendall 1962, p. 47) and employed the battery of computer programs called Statistical Package for the Social Sciences (SPSS: Nie et al. 1975). The total side effect score was recorded as zero if not related to the drug administration, one (mild, on one occasion only, possibly related) up to a maximum of 32 if very severe, continued and definitely related (see earlier under Method and Material). The differences and the statistics are presented in Table 3. Patients treated with lofepramine suffered from the side effects of dry mouth, blurred vision and drowsiness less than patients treated with amitriptyline. The low mean side effects scores recorded at the 4-6 week follow-up appointment
360 TABLE
3
SIDE EFFECTS Side effect
ASSESSED
AS DIFFERENCES
Increase (Lofepramine)
FROM
PRE-TREATMENT
SCORES
Increase (Amitriptyline)
Kendall’s fall (c)
Probability value
Dry mouth 7-10 days 4- 6 weeks
6.22 4.94
10.15 6.63
0.29 0.13
0.04 0.25
Blurred oision 7-10 days 4- 6 weeks
0.65 3.00
3.96 3.14
0.30 0.0 1
0.02 0.48
Drowsiness 7-10 days 4- 6 weeks
4.78 -0.87
7.89 2.75
0.25 0.48
0.07 0.0 1
are affected by the early withdrawal of many of the patients who suffered from severe side effects, and who had high side effects scores at the 7-10 days follow-up appointment. The differences in scores on constipation and on spontaneously mentioned side effects did not reach statistical significance and are not considered in detail here.
Discussion There is a great deal of interest currently in the possibility, with experiments of the type reported here, of making the type II statistical error (Siegel 1956). This error, in the present context, is of failing to detect a real difference between the drugs when in fact one exists. Such an error can arise for a variety of reasons. One possibility is that the sample size was too small for the task. In the present study, have we missed a significant difference in effect that we could have found by using a slightly larger sample? Using a standard statistical method based on the formula for the t-statistic, one may show that given the current degree of variability in the groups, and the particular difference in ZSDS scores, it would have been necessary to have had 541 patients in each group for there to have been a significant difference at the 5% level - a total of 1082 patients in the trial altogether. Alternatively, given the same sample sizes, a difference of at least 7.9 units on the ZSDS scores would have been necessary. Thus it seems fair to conclude that the similarity in therapeutic effect of the two drugs is such that, within the realms of what is practicable, it is difficult to distinguish between them. The tricyclic antidepressants now have an established place in the management of depressive illness, and at present in the U.K. arnitriptyline is the most commonly prescribed of these drugs. In standard therapeutic doses their use is not commonly associated with serious irreversible toxic effects, but patient compliance is often a
361
problem and this may be exacerbated by unpleasant side effects. There is scope for the introduction of further compounds for clinical use if in the new drug the ratio of side effects to therapeutic effect is lower than that of existing drugs. Earlier work has suggested that 35 mg of lofepramine has at least the therapeutic effect of 25 mg amitriptyline (McClelland et al. 1979). The results of the present study are consistent with this view and also suggest that side effects are experienced much less with lofepramine. This was particularly true of drowsiness. The pattern of side effects in the present study was that they were at their peak at 7-10 days and then improved after 4-6 weeks. On lofepramine the early drowsiness completely disappeared, whereas there was still a significant degree of drowsiness present in the average patient on amitriptyline at the end of this period. Lofepramine produced less in the way of dry mouth and blurred vision than amitriptyline, and in the case of these autonomic side effects the difference was most marked after 7-10 days. Other side effects showed no conspicuous difference between the drugs. These results taken at their face value suggest that lofepramine may be an advance in tricyclic medication. Before accepting the findings, however, it is necessary to consider a number of points of methodology. The severity of the depressive illness suffered by patients included in the trial is shown by their ZSDS score prior to treatment. Their mean score of 63 falls within the moderate-markedly depressed range as defined by Zung (Zung 1972). The scientific assessment of side effects is still at a fairly rudimentary stage. It has only recently become accepted practice to assess the patient on key symptoms, which are expected to be potential side effects, at the beginning of the trial and before the drug is administered. We consider this to be of crucial importance for the following reasons. The customary double-blind comparative trial allocates subjects at random to the two treatments. Even with this method it is possible to find ways in which the two groups are significantly different at the beginning of the trial, especially if a large number of variables are carefully scrutinised. An example in the present study was the finding that, though the two groups were comparable on all other measures of severity initially, the complaint of dry mouth was more prevalent in the amitriptyline group to a degree that almost reached statistical significance at the conventional level. Clearly if the absolute levels of side effects had then later been considered, it would have been necessary for the amitriptyline-treated patients to have shown only a slight worsening (compared to the lofepramine group) to have produced an unfairly dramatic result as assessed by inferential statistics and their associated probability values. To avoid this false impression we believe that it is important whenever possible to compare at later dates not the absolute scores of the two groups but the differences (increases or decreases) from the initial scores. A further refinement that we have used in measuring side effects is to assess them on three factors - severity, frequency and relationship to the medication. There is a rational case for this approach. Clearly a severe side effect (in terms of distress or disability) should be rated as worse than a mild one. A persistent side effect should be rated as worse than a transient one. These two aspects are not always separated in
362
discussions on the subject and yet they are not necessarily highly correlated in practice. The concept of relevance is even less often mentioned. In fact it can often be easily determined, both by the patient and the physician, that a new symptom is not attributable to the medication, but to intervening trauma, infection or some other discrete cause. In this case we recommend that even though it be recorded for completeness and scrupulous accuracy, particularly if it sounds similar to expected side effects, then the weighting it is given should be adjusted to ensure that it does not contribute unfairly to the total side effect scores. The interaction of the three factors of severity, frequency and relevance is logically that of products rather than sums, and therefore the final score on a side effect is obtained by multiplying them together. The drop-out rate was particularly high on this trial. One reason for this could be the fact that the method of drug administration adopted was to give each patient the estimated maximum daily dose of antidepressant required right from the beginning (210 mg of lofepramine, 150 mg of amitriptyline). According to the protocol, patients were encouraged to reduce the dose if they found the side effects, unpleasant, and even to stop the drug completely for 24 hours before resuming at a lower dose. This method had worked satisfactorily on previous trials in the hands of one of the authors (e.g. Priest 1976a). However, in retrospect it seems that this method demands a particular commitment on the part of the prescribing doctor, and an especial emphasis to ensure that the patients comply with the procedure. Depressed patients are prone to act in a self-punitive way either by continuing on the high dose when the side effects are excessively troublesome or by discontinuing the medication completely (Priest 1977). Although the method adopted here has advantages when it comes to the statistical interpretation of the results, it may be that it would have been preferable to have used the more common method of starting at a fraction of the estimated maximum dose and increasing gradually as tolerated by the patient. Our difficulty with the latter method is that if a patient ends up on a small dose of medication it is not always easy to assess, when analyzing the results, the extent to which the low dose represents beneficial properties (good response on a small dose) or disadvantages (patient’s reluctance to increase the dose because of side effects). Clearly patients may exaggerate the improvement that has occurred in order to avoid suffering an increase in the dose of medication. At the end of the first week only 17 (out of 27) patients on lofepramine, and only 11 patients (out of 29) on amitriptyline were continuing at the full dose. It will be recalled that by the end of the trial the numbers had dropped to 11 and 7, respectively. These figures are consistent with the findings of greater difficulty with side effects on amitriptyline. Although we had not deliberately set out to achieve a high rate of patient drop out, it is interesting to speculate that the more favourable tolerance of lofepramine might not have been demonstrated so clearly with a gentler introduction to the medication or a lower limit for the full dose.
363
References Eriksoo, E. and Rohte, O., Chemistry and pharmacology of a new potential antidepressant, Arzneim.-Forsch., 20 (1970) 1561-1569. Kendall, M.G., Rank Correlation Methods, Griffin, London, 1962. McClelland, H.A., Kerr, LA., Stephens, D.A. and Howell, R.W., The comparative antidepressant value of lofepramine and amitriptyline, Acta Psychiat. Stand., 60 (1979) 190-198. Nie, N.H., Hull, C.H., Jenkins, J.G., Steinbrummer, K. and Bent, D.H., SPSS - Statistical Package for the Social Sciences, McGraw-Hill, London, 1975. Obermair, W. and Wegener, G., Lofepramine: a new antidepressant - Resume of international clinical trial results, J. Pharmacother., 1 (1978) 108-I 10. Priest, R.G., The Edinburgh homeless - A psychiatric study, Amer. J. Psychotherapy, 25 (1971) 194-213. Priest, R.G., A comparative trial of protriptyline and nortriptyline, Current Med. Res. Opinion, 3 (1976a) 710-715. Priest, R.G., The homeless person and the psychiatric services - An Edinburgh survey, Brit. J. Psychiat., 22 (1976b) 172-175. Priest, R.G., Sadness, hate and suicide. In: A.M. Jukes (Ed.), Depression - The Biochemical and Physiological Role of Ludiomil, Ciba Publications, Metropolis Press, London, 1977. Priest, R.G. and Netter, P., Hostility, somatic symptoms and recovery with antidepressants, Int. Pharmacopsychiat., 10 (1975) 137-141. Priest, R.G. and Woolfson, G., Minski’s Handbook of Psychiatry, Heinemann, London, 1978. Siegel, S., Non-parametric Statistics for the Behavioural Sciences, McGraw-Hill, London, 1956. Zung, W.W.K., A Self Rating Depression Scale, Arch. Gen. Psychiat., 12 (1965) 63-70. Zung, W.W.K., How normal is depression?, Psychosomatics, 13 (1972) 174-178.
Journal of Affective Disorders, 4 (1982) 355-363 Elsevier Biomedical Press
Does Lofepramine
have Fewer Side Effects than Ami trip tyline?
Results
of a Comparatrve
Trial
R. Pugh, Janne Bell, A.J. Cooper, S. Dunstan, D. Greedharry, P. Raptopoulos, Charmian Rowsell, J. Steinert and R.G.
J. Pomeroy, Priest *
Academic Deportment ofPsychiatry,St. Maty’s Hospital, Harrow Road, London W9 3RL. and St. Bernard’s Hospital, Uxbridge Road, Southall, Middlesex UBI 3ElJ (Great Britain) (Received 3 September, 1981) (Revised, received 5 April, 1982) (Accepted 21 April, 1982)
Summary A double blind trial was carried out comparing the tricyclic antidepressant lofepramine with amitriptyline in the treatment of patients suffering from moderate to markedly severe depression. No difference was demonstrated between the two drugs in terms of their antidepressant effect, but patients treated with lofepramine suffered from singificantly less side effects than patients treated with amitriptyline. Both groups of patients had a high drop out rate but this was less marked in the groups of patients treated with lofepramine.
Introduction The efficacy of the tricyclic antidepressant drugs may now be regarded as axiomatic. Particularly striking are the experiments which demonstrate an increased rate of reIapse when placebo is blindly substituted for the active preparation.
* Reprint Britain.
requests
to Professor
0 165-0327/82/0000-0000/$02.75
R.G. Priest, St. Mary’s Hospital,
D I982 Elsevier Biomedical
Harrow
Press
Road, London
W9 3RL, Great
356
Tricyclic antidepressants are widely used in medicine, and in the usual dosage the majority have proved to be relatively free from toxic effects, at least in short-term use. There is now a growing choice of such drugs available (Priest and Woolfson 1978) and it is necessary to evaluate the relative merits of each. Each drug or group of drugs, as it is introduced, must be compared against those previously in use, not only from the point of view of efficacy but also with regard to unpleasant side effects. There is ample reason, therefore, for adopting the comparative trial as a standard procedure. Amitriptyline is now the most commonly prescribed antidepressant in the United Kingdom, and in this study it has been adopted as the reference compound against which to assess the newer preparation lofepramine. Lofepramine is a dibenzapin derivative that differs from imipramine by the substitution of the aliphatic amino group by a 4’-chlorphenacyl group. It has a low toxicity in rats and mice compared with imipramine, desmethylimipramine, amitriptyline, maprotiline, and nomifensine, and the chemistry and pharmacology were first described by Eriksoo and Rohte (1970). Clinical trials elsewhere have suggested that in humans the antidepressant qualities are of acceptable magnitude but that it is less liable to cause adverse reactions (Obermair and Wegener 1978). In England McClelland and his colleagues (1979) have compared lofepramine with amitriptyline, using 35 mg and 25 mg tablets, respectively. They were unable to show a significant difference in their total sample, but noted that those patients with endogenous depression did better on lofepramine. Since it appears that lofepramine is at least as effective as amitriptyline the dosage described we adopted this regime in order to repeat the comparison of efficacy but also to see particularly whether there were conspicuous clinical differences in the amount of side effects produced by these two drugs. Method and Material Selection of subjects A consecutive series of patients was assigned to the trial. The patients comprised all those that arose in the clinical practice of one of us (J.S.) that were diagnosed as suffering from depressive illness and considered for tricyclic antidepressant medication, provided that certain criteria were met: (1) Age 15-75; (2) Either sex; (3) Not pregnant; (4) Not currently under treatment with other psychotropic drugs (except benzodiazepines or small doses of phenothiazines); (5) Depressive symptoms which would normally be treated with drugs by the clinician concerned. Patients were asked to take part in a clinical trial and informed consent was obtained. They took 2 tablets three times daily after meals (i.e. 2 X 35 mg tablets of lofepramine or 2 X 25 mg tablets of amitriptyline, 3 times daily). They were advised that, should side effects prove troublesome, they should omit the medication for 24 hours and then resume it at approximately half the previous level.
357
Assessment Progress was assessed by use of: (1) A global clinical rating scale; (2) Standardised psychological tests. These included the self rating depression scale developed by Zung (Zung 1965; Priest and Netter 1975). This complements the observer rating scale above by being free from observer bias. Assessment was carried out: (a) At the beginning of the trial (when weight and height were measured, and demographic data collected); (b) After 7-10 days; (c) After 4-6 weeks. Side effects Patients were told about possible side effects at the beginning of the trial. At that stage they were rated on pre-existing constipation, dry mouth, etc. to avoid these being mistakenly attributed to the drug (when in fact they are common symptoms of depressive illness). On subsequent occasions they were asked an open-ended question on symptoms that they had interpreted as side effects. They were then rated on a predetermined list of effects that are anticipated in a proportion of subjects taking tricyclic preparations (specifically dry mouth, blurred vision, drowsiness and constipation). For each putative side effect ratings were made (c.f. Priest 1976a) on: (a) relevance, (b) persistence, and (c) intensity, and an integrated index of severity was calculated. Each suspected side effect was rated according to severity (1 = mild, 2 = moderate, 3 = severe, 4 = very severe), frequency (1 = once, 2 = infrequently, 3 = often, 4 = continually) and the relationship that it seemed to bear to the administration of the drug (0 = not related, 1 = possibly related, 2 = definitely related). The index was calculated by multiplying together the scores on a, b and c above for each side effect. This is a slightly modified version of the previously used method (Priest 1976a), the main difference being that since the ‘not related’ category is coded as zero, the effect is to exclude this item from counting as a side effect. The logic of the remaining argument is that relevance, persistence and intensity all have a mutual effect that is best displayed as a product, rather than as a sum, of their individual degrees.
Results (I) General description of patients Altogether 56 patients were taken into the trial, 27 on lofepramine and 29 on amitriptyline. There were 30 drop outs of which 13 were on lofepramine and 17 were on amitriptyline. This difference is not significant (x2 = 0.62, P = 0.11). The age range was from 18 to 68, 15 patients were male and 41 female. There was no significant difference between patients allocated to lofepramine and
358
amitriptyline at the beginning of the trial in age, sex, previous psychiatric history and family history of psychiatric illness. Since depression covers such a wide spectrum it is of importance to other workers to have some idea of the level of severity of the patients in our trial. Before starting treatment the mean score on the Zung Self Rating Depression Scale (ZSDS) Index was 62.75. (2) Lofepramine Zung The ference or after
compared with amitriptyline
Self Rating Depression Scale results from this questionnaire are shown on Table 1. No significant could be shown between the two groups prior to treatment, after 7-10 4-6 weeks.
difdays
Psychiatrists global rating scale The results obtained using this scale are shown on Table2. No significant difference could be shown between the two groups. Thus no significant difference in outcome could be detected either by the psychiatrist global rating scale or by the ZSDS between patients treated with lofepramine and patients treated with amitriptyline. However, there was a difference in the drop out rate on the two drugs. At the 7-10 day assessment, of the 27 allocated to lofepramine 7 had stopped treatment, 3 were continuing at a reduced dose and 17 were continuing at full dose. The equivalent figures for amitriptyline were 9, 9 and 11 (total = 29). At the 4-6 week assessment, of those allocated to lofepramine 13 had stopped treatment, 3 were on a reduced dose and 11 were continuing at full dose. For amitriptyline the figures were 17, 5 and 7, respectively. There is clearly a trend in favour of lofepramine patients perservering more with their medication, but statistical significance is achieved only at the 7-10 day assessment (tau = 0.18, P < 0.05). TABLE
1
ZUNG
SELF RATING
DEPRESSION
SCALE
High score = severe depression. Mean scores
Score prior to treatment Score at 7-10 days Score at 4-6 weeks
Student’s
Lofepramine
Amitriptyline
I
P
61.62 63.17 56.20
63.89 64.63 59.31
0.51 0.36 0.71
0.6 1 0.72 0.48
0.28 0.25
0.778 0.805
Difference between scores prior to treatment Score at 7- 10 days 0.333 Score at 4-6 weeks 3.928
and the 1.937 5.08
359
TABLE
2
PSYCHIATRIST
GLOBAL
RATING
SCALE
High score = less severe. Mean scores
Score prior to treatment Score at 7- 10 days Score at 4-6 weeks
Student’s
Lofepramine
Amitriptyline
t
P
2.78 3.71 3.61
2.75 3.13 3.00
0.11
0.91 0.31 0.23
1.04 1.24
(3) Side effects In constrast to the lack of significant difference in therapeutic effect, a number of important differences in the incidence of side effects was found. We took two precautions before accepting them as valid. Firstly we subtracted the pre-trial scores obtained on such complaints as dry mouth and constipation. Secondly we used non-parametric statistics to infer probability values. Subtraction of the initial scores is now a recognised practice, and takes into account symptoms of the presenting depressive illness, including the high prevalence of dry mouth, constipation and other potential side effects. The need for non-parametric statistics arises from the nature of the data (Siegel 1956). The side effect ratings (and the differences derived from them by subtraction) cannot be considered as equal interval scales (in contrast to age, in which someone of 60 years may be justifiably regarded as twice as old as someone of 30 years). The ratings may be regarded, however, as representing the ordinal level of measurement. For instance, with a rating scale which goes from 1 (mild) to 4 (severe) one may assume that a person in category 4 is worse than one in category 2, but not necessarily twice as badly off. We have used Kendall’s tau as the statistic for dealing with this data. The case for using this with survey data has been argued before (Priest 1971, 1976b). Kendall’s tau is a rank order correlation coefficient that makes no assumptions about the distribution of the data (other than that they can be seen as categories ranked in order), and it does not pay undue attention to outlying values. We favoured tau (c) as recommended for oblong tables (Kendall 1962, p. 47) and employed the battery of computer programs called Statistical Package for the Social Sciences (SPSS: Nie et al. 1975). The total side effect score was recorded as zero if not related to the drug administration, one (mild, on one occasion only, possibly related) up to a maximum of 32 if very severe, continued and definitely related (see earlier under Method and Material). The differences and the statistics are presented in Table 3. Patients treated with lofepramine suffered from the side effects of dry mouth, blurred vision and drowsiness less than patients treated with amitriptyline. The low mean side effects scores recorded at the 4-6 week follow-up appointment
360 TABLE
3
SIDE EFFECTS Side effect
ASSESSED
AS DIFFERENCES
Increase (Lofepramine)
FROM
PRE-TREATMENT
SCORES
Increase (Amitriptyline)
Kendall’s fall (c)
Probability value
Dry mouth 7-10 days 4- 6 weeks
6.22 4.94
10.15 6.63
0.29 0.13
0.04 0.25
Blurred oision 7-10 days 4- 6 weeks
0.65 3.00
3.96 3.14
0.30 0.0 1
0.02 0.48
Drowsiness 7-10 days 4- 6 weeks
4.78 -0.87
7.89 2.75
0.25 0.48
0.07 0.0 1
are affected by the early withdrawal of many of the patients who suffered from severe side effects, and who had high side effects scores at the 7-10 days follow-up appointment. The differences in scores on constipation and on spontaneously mentioned side effects did not reach statistical significance and are not considered in detail here.
Discussion There is a great deal of interest currently in the possibility, with experiments of the type reported here, of making the type II statistical error (Siegel 1956). This error, in the present context, is of failing to detect a real difference between the drugs when in fact one exists. Such an error can arise for a variety of reasons. One possibility is that the sample size was too small for the task. In the present study, have we missed a significant difference in effect that we could have found by using a slightly larger sample? Using a standard statistical method based on the formula for the t-statistic, one may show that given the current degree of variability in the groups, and the particular difference in ZSDS scores, it would have been necessary to have had 541 patients in each group for there to have been a significant difference at the 5% level - a total of 1082 patients in the trial altogether. Alternatively, given the same sample sizes, a difference of at least 7.9 units on the ZSDS scores would have been necessary. Thus it seems fair to conclude that the similarity in therapeutic effect of the two drugs is such that, within the realms of what is practicable, it is difficult to distinguish between them. The tricyclic antidepressants now have an established place in the management of depressive illness, and at present in the U.K. arnitriptyline is the most commonly prescribed of these drugs. In standard therapeutic doses their use is not commonly associated with serious irreversible toxic effects, but patient compliance is often a
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problem and this may be exacerbated by unpleasant side effects. There is scope for the introduction of further compounds for clinical use if in the new drug the ratio of side effects to therapeutic effect is lower than that of existing drugs. Earlier work has suggested that 35 mg of lofepramine has at least the therapeutic effect of 25 mg amitriptyline (McClelland et al. 1979). The results of the present study are consistent with this view and also suggest that side effects are experienced much less with lofepramine. This was particularly true of drowsiness. The pattern of side effects in the present study was that they were at their peak at 7-10 days and then improved after 4-6 weeks. On lofepramine the early drowsiness completely disappeared, whereas there was still a significant degree of drowsiness present in the average patient on amitriptyline at the end of this period. Lofepramine produced less in the way of dry mouth and blurred vision than amitriptyline, and in the case of these autonomic side effects the difference was most marked after 7-10 days. Other side effects showed no conspicuous difference between the drugs. These results taken at their face value suggest that lofepramine may be an advance in tricyclic medication. Before accepting the findings, however, it is necessary to consider a number of points of methodology. The severity of the depressive illness suffered by patients included in the trial is shown by their ZSDS score prior to treatment. Their mean score of 63 falls within the moderate-markedly depressed range as defined by Zung (Zung 1972). The scientific assessment of side effects is still at a fairly rudimentary stage. It has only recently become accepted practice to assess the patient on key symptoms, which are expected to be potential side effects, at the beginning of the trial and before the drug is administered. We consider this to be of crucial importance for the following reasons. The customary double-blind comparative trial allocates subjects at random to the two treatments. Even with this method it is possible to find ways in which the two groups are significantly different at the beginning of the trial, especially if a large number of variables are carefully scrutinised. An example in the present study was the finding that, though the two groups were comparable on all other measures of severity initially, the complaint of dry mouth was more prevalent in the amitriptyline group to a degree that almost reached statistical significance at the conventional level. Clearly if the absolute levels of side effects had then later been considered, it would have been necessary for the amitriptyline-treated patients to have shown only a slight worsening (compared to the lofepramine group) to have produced an unfairly dramatic result as assessed by inferential statistics and their associated probability values. To avoid this false impression we believe that it is important whenever possible to compare at later dates not the absolute scores of the two groups but the differences (increases or decreases) from the initial scores. A further refinement that we have used in measuring side effects is to assess them on three factors - severity, frequency and relationship to the medication. There is a rational case for this approach. Clearly a severe side effect (in terms of distress or disability) should be rated as worse than a mild one. A persistent side effect should be rated as worse than a transient one. These two aspects are not always separated in
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discussions on the subject and yet they are not necessarily highly correlated in practice. The concept of relevance is even less often mentioned. In fact it can often be easily determined, both by the patient and the physician, that a new symptom is not attributable to the medication, but to intervening trauma, infection or some other discrete cause. In this case we recommend that even though it be recorded for completeness and scrupulous accuracy, particularly if it sounds similar to expected side effects, then the weighting it is given should be adjusted to ensure that it does not contribute unfairly to the total side effect scores. The interaction of the three factors of severity, frequency and relevance is logically that of products rather than sums, and therefore the final score on a side effect is obtained by multiplying them together. The drop-out rate was particularly high on this trial. One reason for this could be the fact that the method of drug administration adopted was to give each patient the estimated maximum daily dose of antidepressant required right from the beginning (210 mg of lofepramine, 150 mg of amitriptyline). According to the protocol, patients were encouraged to reduce the dose if they found the side effects, unpleasant, and even to stop the drug completely for 24 hours before resuming at a lower dose. This method had worked satisfactorily on previous trials in the hands of one of the authors (e.g. Priest 1976a). However, in retrospect it seems that this method demands a particular commitment on the part of the prescribing doctor, and an especial emphasis to ensure that the patients comply with the procedure. Depressed patients are prone to act in a self-punitive way either by continuing on the high dose when the side effects are excessively troublesome or by discontinuing the medication completely (Priest 1977). Although the method adopted here has advantages when it comes to the statistical interpretation of the results, it may be that it would have been preferable to have used the more common method of starting at a fraction of the estimated maximum dose and increasing gradually as tolerated by the patient. Our difficulty with the latter method is that if a patient ends up on a small dose of medication it is not always easy to assess, when analyzing the results, the extent to which the low dose represents beneficial properties (good response on a small dose) or disadvantages (patient’s reluctance to increase the dose because of side effects). Clearly patients may exaggerate the improvement that has occurred in order to avoid suffering an increase in the dose of medication. At the end of the first week only 17 (out of 27) patients on lofepramine, and only 11 patients (out of 29) on amitriptyline were continuing at the full dose. It will be recalled that by the end of the trial the numbers had dropped to 11 and 7, respectively. These figures are consistent with the findings of greater difficulty with side effects on amitriptyline. Although we had not deliberately set out to achieve a high rate of patient drop out, it is interesting to speculate that the more favourable tolerance of lofepramine might not have been demonstrated so clearly with a gentler introduction to the medication or a lower limit for the full dose.
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References Eriksoo, E. and Rohte, O., Chemistry and pharmacology of a new potential antidepressant, Arzneim.-Forsch., 20 (1970) 1561-1569. Kendall, M.G., Rank Correlation Methods, Griffin, London, 1962. McClelland, H.A., Kerr, LA., Stephens, D.A. and Howell, R.W., The comparative antidepressant value of lofepramine and amitriptyline, Acta Psychiat. Stand., 60 (1979) 190-198. Nie, N.H., Hull, C.H., Jenkins, J.G., Steinbrummer, K. and Bent, D.H., SPSS - Statistical Package for the Social Sciences, McGraw-Hill, London, 1975. Obermair, W. and Wegener, G., Lofepramine: a new antidepressant - Resume of international clinical trial results, J. Pharmacother., 1 (1978) 108-I 10. Priest, R.G., The Edinburgh homeless - A psychiatric study, Amer. J. Psychotherapy, 25 (1971) 194-213. Priest, R.G., A comparative trial of protriptyline and nortriptyline, Current Med. Res. Opinion, 3 (1976a) 710-715. Priest, R.G., The homeless person and the psychiatric services - An Edinburgh survey, Brit. J. Psychiat., 22 (1976b) 172-175. Priest, R.G., Sadness, hate and suicide. In: A.M. Jukes (Ed.), Depression - The Biochemical and Physiological Role of Ludiomil, Ciba Publications, Metropolis Press, London, 1977. Priest, R.G. and Netter, P., Hostility, somatic symptoms and recovery with antidepressants, Int. Pharmacopsychiat., 10 (1975) 137-141. Priest, R.G. and Woolfson, G., Minski’s Handbook of Psychiatry, Heinemann, London, 1978. Siegel, S., Non-parametric Statistics for the Behavioural Sciences, McGraw-Hill, London, 1956. Zung, W.W.K., A Self Rating Depression Scale, Arch. Gen. Psychiat., 12 (1965) 63-70. Zung, W.W.K., How normal is depression?, Psychosomatics, 13 (1972) 174-178.