Br. J. c/in. Pharm. (1977), 4, 153S-156S
CONTRASTS IN ANTIDEPRESSANT MEDICATIONS J.R. WITTENBORN Rutgers University, New Brunswick, New Jersey, USA
Two studies are reviewed, one in depressed patients, the other in healthy volunteers. 2 The effect of nomifensine and imipramine on depressed out-patients has been studied in a controlled double-blind manner. Treatment lasted for 4 weeks and assessments were carried out before and at weekly intervals during the study. These involved use of a self-rating scale and four observer rating scales. 3 In the self-rating scale, 13 of the 14 discriminating items favoured nomifensine, and indicated that it possessed a strengthening or energizing activity, and analysis of individual items on the Hamilton Depression Scale confirmed this. 4 In this study, imipramine showed greater effect on mood and on sleep disturbances. 5 A comparison of nomifensine, imipramine and placebo was carried out in 90 volunteers in a double-blind randomized study. Each volunteer received three doses of medication during the study day. 6 The assessments include a Digit Symbol Substitution Test, the production of a temporal interval, and a simple and a complex test of attention or vigilance. 7 The influence of nomifensine on these tests could not be distinguished from that of placebo. There was evidence, however, that imipramine depressed performance and possessed a sedative effect. 8 The results of both studies, when considered together, are essentially in agreement. 1
Introduction
Two recent studies indicate that nomifensine may be expected to have a different profile of effects from imipramine. If these indications are sustained by future clinical research, an important specificity could be realized in the use of psychotropic substances in the management of depressive episodes. Study I
Depressed outpatients An analysis (Patrick & Frey, 1976) of data on 54 depressed out-patients shows nomifensine to have had a pattern of effect different from that of imipramine. The data were gathered under double-blind conventions; after a pretreatment wash-out of I week, standard assessments were carried out on days 1, 7, 14, 21 and 28. The average age of the patients was 32 yr, and 80% were women. Fifty-two per cent of the patients were or had been employed in a white collar capacity and 74% had finished secondary school. The average duration of the current episod; was 8 weeks, and for 30% of the patients the current episode was described as a recurrence of a former condition. Half of the sample had never had psychiatric treatment before the 8
present episode, and 35% of the patients had been employed most, if not all, of the time during the past three years. The formal assessment of the patients' symptomatic status during the course of treatment included a selfrating scale (the Self Rating Symptom Scale) and four observer rating scales (the Hamilton Depression Scale, the Hamilton Anxiety Scale, the Brief Psychiatric Rating Scale (BPRS), and the Investigator's Global Impression). All assessments were made on days 1 and 28 of treatment, and the Self-Rating Symptom Scale and the Hamilton Depression Scale were administered on a weekly schedule. In addition to the symptomatic assessment, the programme included the repeated administration of a standard physical examination, including the usual vital signs, laboratory testing with standard haematology and differential determinations, and urinalysis, including microscopic examination, and blood chemistry. Results
The medication groups were compared in terms of residual scores, which examined differences at each
154S J.R. WITTENBORN assessment period after corrections were made for pretreatment differences. These examinations were carried out for each item included in the various assessment devices and for summarizing factor scores
well. With the exception of very few items, such as "sweating" and "hot and cold spells", the various items and summarizing scores indicated remissive trends throughout the treatment period. In terms of the residual score comparison, the SelfRating Symptom Scale showed more significant contrasts than would have been expected on the basis of chance alone, and 13 of the 14 discriminating items favoured nomifensine. Most of the contrasts were found on day 7. The nomifensine group showed greater remission with respect to such items as "low energy," "numbness," "heavy feeling," "dizziness," and "loss of sex interest." One item, "trouble sleeping," showed a greater remissive change to have occurred in the imipramine group. None of the 13 items that showed the greater remissive trend to have occurred in the nomifensine group refers to a clearly affective aspect of depression. Most of the items seem to imply a strengthening or energizing function. When the items of the Hamilton Depression Scale were examined, it was found that the nomifensine group showed the greater remissive changes in "retardation," "disturbance in work," and "weight loss." The imipramine group showed the greater remissive change with respect to such affectively significant items as "depressed," "psychic anxiety," and "psychasthenia." In addition, there was a persistent advantage for the imipramine group in remission of "sleeping difficulties." Thus, the Hamilton Depression Scale, like the Self-Rating Symptom Scale, suggests that nomifensine is conspicuous, not because of its affective consequences but because of a kind of implementing, energizing function. In contrast, imipramine was associated with the greater remissive affective changes and with improved sleep. The Hamilton Anxiety Scale and the BPRS were not administered on days 7, 14 and 21, and as a consequence could not show the prompt contrast that the Self-Rating Symptom Scale showed. The Anxiety Scale was not discriminating, but the BPRS showed a greater reduction in "unusual thought content," "conceptual disorganization," and "excitement" in the nomifensine group than in the imipramine group. The imipramine group, however, showed the greater diminution in "depressive mood". In the present sample of remitting depressed outpatients, it is apparent that nomifensine is associated with improved physical and mental functioning, whereas imipramine is associated with relief of depressive affect and disturbances of sleep. These contrasts describe differentiating therapeutic effects that could be useful considerations in the choice of alternative antidepressant medications. Replicative
studies based on independent samples will confirm or repudiate this interesting clinical possibility. Study 2
as
Normal volunteers These contrasts are reminiscent of some recently described differences between the psychomotor consequences of nomifensine and of imipramine in a sample of normal male paid volunteers (Wittenborn et al., 1976). This study was concerned with the issue of behavioural toxicity consequent to pharmacotherapy and sought to examine any detracting psychomotor effects of these antidepressant medications during the initial day of treatment. In a sample of depressed patients, an effective medication could have a detracting effect on psychomotor performance while contributing to motivational improvement. Thus, behavioural improvement due to motivational and other treatment-related affective gains could obscure, if not confound, any treatment-induced impairment in psychomotor potential. To minimize, if not eliminate, the contribution of motivational and affective improvement on psychomotor behaviour, normal volunteers were preferred (Wittenborn, 1977) for this scrutiny of psychomotor consequences per se.
Methods A one-day trial was carried out with assessments of psychomotor performance beginning at 0800 and repeated in a standard manner on an hourly basis until the end of the day 9 h later. After the initial assessment at 0800, the subjects received nomifensine 50 mg, imipramine 50 mg, or an indistinguishable placebo on the basis of random double-blind assignment. Three hours later, between 1100 and 1200, the subject received a second dosage unit and after an additional 3 h, he received the third identicai unit of medication. Thus, by mid-afternoon he had received a total of 150 mg, which is a standard initial medication and within the therapeutic range. The assessment included the Digit Symbol Substitution Test (DSST), the production of a temporal interval, both a simple and a complex test of attention or vigilance, and other tests which were less sensitive to the differences between the psychomotor effects of the medications. Each of the 30-min assessment periods was separated by a supervised rest period. The production of a temporal interval is a most simple procedure wherein the subject is asked to depress a key for what he estimates to be a specified period of time, for example, a 10-s interval. He does this without recourse to any standard and does not have access to a watch or other timing devices during the course of the day. During each hourly testing
ANTIDEPRESSANT MEDICATIONS
1558
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I' 8 10.0 1
I
2
3
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4
5 6 7 Session
8
9
10
'a
2
Figure 1 Estimate of a 10-s interval (fourth in block of five). 0, Placebo; A, imipramine; *, nomifensine.
session, he is asked to produce a 10-s interval on five successive occasions. The normal response to this situation is to produce an appreciably longer temporal interval than requested. This is illustrated in Figure 1, which shows the exaggerated duration of the intervals produced by the placebo group. The performance of the nomifensine group was indistinguishable from that of the placebo group, but the exaggeration was diminished in the imipramine group and the intervals produced were significantly nearer to the 10-s interval required. Thus, imipramine tends to correct a normal error in the estimation of a temporal interval and suggests that in the subjects receiving imipramine, judgment of the passage of time was modified in a way that was not apparent among the subjects receiving nomifensine. The latency of pressing a button in response to the appearance of the letter X as it occurred in random sequence of illuminated letters was substantially increased among the subjects receiving imipramine. In contrast, the latency of response among subjects
3
4
5
6 7 Session
8
9
10
Figure 3 Complex vigilance test: latency of correct responses. 0, Placebo; A, imipramine; *, nomifensine.
receiving nomifensine or placebo was unmodified. Thus, latency of response in the simple vigilance test further attests to the fact that there is some disturbance in the temporal aspects of the behaviour of subjects receiving imipramine (Figure 2). A complex vigilance test, wherein the subject must consider not only the letter presented but also the preceding letter, was most discriminating. Depressing the response button was affected in the imipramine group, but the performances of the nomifensine and the placebo subjects were indistinguishable and seemingly unimpaired. Imipramine not only increased the latency of the responses, but it also impaired the accuracy of response. This is illustrated by Figures 3 and 4, which 82
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Session Figure 2 responses.
o,
Simple vigilance test: latency of correct Placebo; A, imipramine; *, nomifensine.
Session Figure 4 responses.
Complex vigilance test: number of correct Placebo; A, imipramine; *, nomifensine.
0,
1568 J.R. WITTENBORN
show the performance of the nomifensine and placebo subjects to be indistinguishable, whereas the imipramine subjects show a significant increase in latency and a reduction in the number of correct responses. During the course of the day, 30 of the 90 volunteer subjects reported that they were sleepy. Six of these were in the placebo group, seven in the nomifensine group, and 17 were receiving imipramine. The increased latency of responses among imipramine subjects, combined with their drowsiness, confirms the sedative, hypnotic effects indicated in the clinical trial data contributed by Patrick & Frey (1976). The psychomotor comparison provided other indications (fewer attempts on the DSST) that, relative to the placebo group, the productive psychomotor output was significantly diminished in the imipramine group, whereas the contrasts between placebo and nomifensine did not become statistically significant.
Discussion
When these two studies are considered together, several interesting conclusions may be tentatively suggested: Nomifensine does not detract from psychomotor performance and in depressed patients seems to be associated with a greater remissive enhancement of general performance than is
imipramine. In both patients and normal subjects, imipramine has an hypnotic effect that was not indicated for nomifensine. In patients, imipramine has a greater mood-elevating effect than does nomifensine. The nature of depressive manifestations can vary from patient to patient. In some, the conspicuous features are primarily affective; in others, anergia and impaired performance are present. If the pattern indicated by the present studies is verified by independent inquiry, imipramine would seem to be preferable in primarily affective dysphorias, particularly when accompanied by disturbance of sleep. When the depression is characterized by anergia and impaired performance, nomifensine would be preferable. Among out-patients, particularly, special note should be made of the detracting psychomotor consequences of imipramine. These effects could suggest precautionary limitation of patients' activity where reliability of psychomotor performance is critical. In patients, in most respects, the effects of these two medications are indistinguishable, and in time it may be found that they are equally applicable to the requirements of many patients. The data described in the present report were gathered under grants from Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey.
References PATRICK, R.O. & FREY, H. (1976). Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey. WITTENBORN. J.R., FLAHERTY, C.F., MCGOUGH, W.E., BOSSANGE, K.A. & NASH, R.J. (1976). A comparison of the effect of imipramine, nomifensine, and placebo on the psychomotor performance of normal
males. Psychopharmacology, 51, 85-90. WITTENBORN, J.R. (1977). Behavioural toxicity in normal humans as a model for assessing behavioural In A Review of toxicity in patients. Psychopharmacology: A Second Decade of Progress, ed. DiMascio, A. New York: Raven (in press).
CONTRASTS IN ANTIDEPRESSANT MEDICATIONS J.R. WITTENBORN Rutgers University, New Brunswick, New Jersey, USA
Two studies are reviewed, one in depressed patients, the other in healthy volunteers. 2 The effect of nomifensine and imipramine on depressed out-patients has been studied in a controlled double-blind manner. Treatment lasted for 4 weeks and assessments were carried out before and at weekly intervals during the study. These involved use of a self-rating scale and four observer rating scales. 3 In the self-rating scale, 13 of the 14 discriminating items favoured nomifensine, and indicated that it possessed a strengthening or energizing activity, and analysis of individual items on the Hamilton Depression Scale confirmed this. 4 In this study, imipramine showed greater effect on mood and on sleep disturbances. 5 A comparison of nomifensine, imipramine and placebo was carried out in 90 volunteers in a double-blind randomized study. Each volunteer received three doses of medication during the study day. 6 The assessments include a Digit Symbol Substitution Test, the production of a temporal interval, and a simple and a complex test of attention or vigilance. 7 The influence of nomifensine on these tests could not be distinguished from that of placebo. There was evidence, however, that imipramine depressed performance and possessed a sedative effect. 8 The results of both studies, when considered together, are essentially in agreement. 1
Introduction
Two recent studies indicate that nomifensine may be expected to have a different profile of effects from imipramine. If these indications are sustained by future clinical research, an important specificity could be realized in the use of psychotropic substances in the management of depressive episodes. Study I
Depressed outpatients An analysis (Patrick & Frey, 1976) of data on 54 depressed out-patients shows nomifensine to have had a pattern of effect different from that of imipramine. The data were gathered under double-blind conventions; after a pretreatment wash-out of I week, standard assessments were carried out on days 1, 7, 14, 21 and 28. The average age of the patients was 32 yr, and 80% were women. Fifty-two per cent of the patients were or had been employed in a white collar capacity and 74% had finished secondary school. The average duration of the current episod; was 8 weeks, and for 30% of the patients the current episode was described as a recurrence of a former condition. Half of the sample had never had psychiatric treatment before the 8
present episode, and 35% of the patients had been employed most, if not all, of the time during the past three years. The formal assessment of the patients' symptomatic status during the course of treatment included a selfrating scale (the Self Rating Symptom Scale) and four observer rating scales (the Hamilton Depression Scale, the Hamilton Anxiety Scale, the Brief Psychiatric Rating Scale (BPRS), and the Investigator's Global Impression). All assessments were made on days 1 and 28 of treatment, and the Self-Rating Symptom Scale and the Hamilton Depression Scale were administered on a weekly schedule. In addition to the symptomatic assessment, the programme included the repeated administration of a standard physical examination, including the usual vital signs, laboratory testing with standard haematology and differential determinations, and urinalysis, including microscopic examination, and blood chemistry. Results
The medication groups were compared in terms of residual scores, which examined differences at each
154S J.R. WITTENBORN assessment period after corrections were made for pretreatment differences. These examinations were carried out for each item included in the various assessment devices and for summarizing factor scores
well. With the exception of very few items, such as "sweating" and "hot and cold spells", the various items and summarizing scores indicated remissive trends throughout the treatment period. In terms of the residual score comparison, the SelfRating Symptom Scale showed more significant contrasts than would have been expected on the basis of chance alone, and 13 of the 14 discriminating items favoured nomifensine. Most of the contrasts were found on day 7. The nomifensine group showed greater remission with respect to such items as "low energy," "numbness," "heavy feeling," "dizziness," and "loss of sex interest." One item, "trouble sleeping," showed a greater remissive change to have occurred in the imipramine group. None of the 13 items that showed the greater remissive trend to have occurred in the nomifensine group refers to a clearly affective aspect of depression. Most of the items seem to imply a strengthening or energizing function. When the items of the Hamilton Depression Scale were examined, it was found that the nomifensine group showed the greater remissive changes in "retardation," "disturbance in work," and "weight loss." The imipramine group showed the greater remissive change with respect to such affectively significant items as "depressed," "psychic anxiety," and "psychasthenia." In addition, there was a persistent advantage for the imipramine group in remission of "sleeping difficulties." Thus, the Hamilton Depression Scale, like the Self-Rating Symptom Scale, suggests that nomifensine is conspicuous, not because of its affective consequences but because of a kind of implementing, energizing function. In contrast, imipramine was associated with the greater remissive affective changes and with improved sleep. The Hamilton Anxiety Scale and the BPRS were not administered on days 7, 14 and 21, and as a consequence could not show the prompt contrast that the Self-Rating Symptom Scale showed. The Anxiety Scale was not discriminating, but the BPRS showed a greater reduction in "unusual thought content," "conceptual disorganization," and "excitement" in the nomifensine group than in the imipramine group. The imipramine group, however, showed the greater diminution in "depressive mood". In the present sample of remitting depressed outpatients, it is apparent that nomifensine is associated with improved physical and mental functioning, whereas imipramine is associated with relief of depressive affect and disturbances of sleep. These contrasts describe differentiating therapeutic effects that could be useful considerations in the choice of alternative antidepressant medications. Replicative
studies based on independent samples will confirm or repudiate this interesting clinical possibility. Study 2
as
Normal volunteers These contrasts are reminiscent of some recently described differences between the psychomotor consequences of nomifensine and of imipramine in a sample of normal male paid volunteers (Wittenborn et al., 1976). This study was concerned with the issue of behavioural toxicity consequent to pharmacotherapy and sought to examine any detracting psychomotor effects of these antidepressant medications during the initial day of treatment. In a sample of depressed patients, an effective medication could have a detracting effect on psychomotor performance while contributing to motivational improvement. Thus, behavioural improvement due to motivational and other treatment-related affective gains could obscure, if not confound, any treatment-induced impairment in psychomotor potential. To minimize, if not eliminate, the contribution of motivational and affective improvement on psychomotor behaviour, normal volunteers were preferred (Wittenborn, 1977) for this scrutiny of psychomotor consequences per se.
Methods A one-day trial was carried out with assessments of psychomotor performance beginning at 0800 and repeated in a standard manner on an hourly basis until the end of the day 9 h later. After the initial assessment at 0800, the subjects received nomifensine 50 mg, imipramine 50 mg, or an indistinguishable placebo on the basis of random double-blind assignment. Three hours later, between 1100 and 1200, the subject received a second dosage unit and after an additional 3 h, he received the third identicai unit of medication. Thus, by mid-afternoon he had received a total of 150 mg, which is a standard initial medication and within the therapeutic range. The assessment included the Digit Symbol Substitution Test (DSST), the production of a temporal interval, both a simple and a complex test of attention or vigilance, and other tests which were less sensitive to the differences between the psychomotor effects of the medications. Each of the 30-min assessment periods was separated by a supervised rest period. The production of a temporal interval is a most simple procedure wherein the subject is asked to depress a key for what he estimates to be a specified period of time, for example, a 10-s interval. He does this without recourse to any standard and does not have access to a watch or other timing devices during the course of the day. During each hourly testing
ANTIDEPRESSANT MEDICATIONS
1558
cf 13.0 lr
CD E e 12.5 iF
4
OCn .-
n 12.0 .~_E C 11.5
) o
r
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CU -'
11.0 IF
0a)
10.5
a)
c
4 )0 '
I' 8 10.0 1
I
2
3
I-
4
5 6 7 Session
8
9
10
'a
2
Figure 1 Estimate of a 10-s interval (fourth in block of five). 0, Placebo; A, imipramine; *, nomifensine.
session, he is asked to produce a 10-s interval on five successive occasions. The normal response to this situation is to produce an appreciably longer temporal interval than requested. This is illustrated in Figure 1, which shows the exaggerated duration of the intervals produced by the placebo group. The performance of the nomifensine group was indistinguishable from that of the placebo group, but the exaggeration was diminished in the imipramine group and the intervals produced were significantly nearer to the 10-s interval required. Thus, imipramine tends to correct a normal error in the estimation of a temporal interval and suggests that in the subjects receiving imipramine, judgment of the passage of time was modified in a way that was not apparent among the subjects receiving nomifensine. The latency of pressing a button in response to the appearance of the letter X as it occurred in random sequence of illuminated letters was substantially increased among the subjects receiving imipramine. In contrast, the latency of response among subjects
3
4
5
6 7 Session
8
9
10
Figure 3 Complex vigilance test: latency of correct responses. 0, Placebo; A, imipramine; *, nomifensine.
receiving nomifensine or placebo was unmodified. Thus, latency of response in the simple vigilance test further attests to the fact that there is some disturbance in the temporal aspects of the behaviour of subjects receiving imipramine (Figure 2). A complex vigilance test, wherein the subject must consider not only the letter presented but also the preceding letter, was most discriminating. Depressing the response button was affected in the imipramine group, but the performances of the nomifensine and the placebo subjects were indistinguishable and seemingly unimpaired. Imipramine not only increased the latency of the responses, but it also impaired the accuracy of response. This is illustrated by Figures 3 and 4, which 82
7; 8 .: C
Y
C
CUa)
) C
5or
,,
49
iCL.
48
720
8
76-
8-
47 &I
-E 46
a) 0
72-
.0
._
CU a)o2
C
45
70-
Ccl
44
a)DC
43'
2
1
3
4
5
6
7
8
9
68-
10
Session Figure 2 responses.
o,
Simple vigilance test: latency of correct Placebo; A, imipramine; *, nomifensine.
Session Figure 4 responses.
Complex vigilance test: number of correct Placebo; A, imipramine; *, nomifensine.
0,
1568 J.R. WITTENBORN
show the performance of the nomifensine and placebo subjects to be indistinguishable, whereas the imipramine subjects show a significant increase in latency and a reduction in the number of correct responses. During the course of the day, 30 of the 90 volunteer subjects reported that they were sleepy. Six of these were in the placebo group, seven in the nomifensine group, and 17 were receiving imipramine. The increased latency of responses among imipramine subjects, combined with their drowsiness, confirms the sedative, hypnotic effects indicated in the clinical trial data contributed by Patrick & Frey (1976). The psychomotor comparison provided other indications (fewer attempts on the DSST) that, relative to the placebo group, the productive psychomotor output was significantly diminished in the imipramine group, whereas the contrasts between placebo and nomifensine did not become statistically significant.
Discussion
When these two studies are considered together, several interesting conclusions may be tentatively suggested: Nomifensine does not detract from psychomotor performance and in depressed patients seems to be associated with a greater remissive enhancement of general performance than is
imipramine. In both patients and normal subjects, imipramine has an hypnotic effect that was not indicated for nomifensine. In patients, imipramine has a greater mood-elevating effect than does nomifensine. The nature of depressive manifestations can vary from patient to patient. In some, the conspicuous features are primarily affective; in others, anergia and impaired performance are present. If the pattern indicated by the present studies is verified by independent inquiry, imipramine would seem to be preferable in primarily affective dysphorias, particularly when accompanied by disturbance of sleep. When the depression is characterized by anergia and impaired performance, nomifensine would be preferable. Among out-patients, particularly, special note should be made of the detracting psychomotor consequences of imipramine. These effects could suggest precautionary limitation of patients' activity where reliability of psychomotor performance is critical. In patients, in most respects, the effects of these two medications are indistinguishable, and in time it may be found that they are equally applicable to the requirements of many patients. The data described in the present report were gathered under grants from Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey.
References PATRICK, R.O. & FREY, H. (1976). Hoechst-Roussel Pharmaceuticals Inc., Somerville, New Jersey. WITTENBORN. J.R., FLAHERTY, C.F., MCGOUGH, W.E., BOSSANGE, K.A. & NASH, R.J. (1976). A comparison of the effect of imipramine, nomifensine, and placebo on the psychomotor performance of normal
males. Psychopharmacology, 51, 85-90. WITTENBORN, J.R. (1977). Behavioural toxicity in normal humans as a model for assessing behavioural In A Review of toxicity in patients. Psychopharmacology: A Second Decade of Progress, ed. DiMascio, A. New York: Raven (in press).
