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Symptom reduction in depressed outpatients treated with amitriptyline or maprotiline: Repeated measurement analysis
Symptom Reduction in Depressed Outpatients Treated With Amitriptyline or M aprotiline: Repeated Measurement Analysis Brigitte
A. Prusoff,
Myrna
M. Weissman,
Janis Tanner.
and Julian
Lieb
P
maprotiline RELIMINARY open-labeled studies ’ had characterized (LudiomiP) as a tetracyclic antidepressant that enhanced both mood and drive, reduced the symptoms of agitation and retardation, and had a fast onset of action. These effects might appear in patients as an increased interest in the environment and decreased apathy during the initial weeks of treatment. To test this observation, maprotiline was compared to amitriptyline hydrochloride (ElaviP ), a conventional tricyclic, in a 4-week double-blind clinical trial with outpatient depressives. No difference between these two compounds in timing of response, efficacy, or side effects was shown after 1 week of treatment or at the completion of the triaL2 when utilizing a standard analysis of covariance. Using a repeated measurement analysis, we then examined the differences in rates of change between the drugs. Since the repeated measurement analysis uses the total period of observation instead of discrete points in time, it may be more sensitive to detecting those differences that were hypothesized prior to initiating the study. This paper will demonstrate the use of repeated measurement analysis to compare rates, pattern, and timing of symptom change between maprotiline and amitriptyline over the 4 weeks of treatment.
MATERIALS
AND
METHODS
Subjects Subjects were between the ages of 21 and 65 (mean age of 36). exhibiting a primary depressive disorder that reached a score of at least 7 on the Raskin Three-Area Scale (range 3- 15). which measures verbal report, behavior, and secondary symptoms of depression..’ A majority of patients (89%) were given a diagnosis of depressive neurosis; the remaining few patients were diagnosed as psychotic depression. Full details of the sample and criteria for selection and exclusion have been described elsewhereP
From the Yale University School of Medicine, Departmenr of Pspchiatr~. Depression Research Unit, New Haven, Corm. Brigitte A. Prusoff. M.P.H.: ,4ssistanl ProJe~sor, Yale l’nivrr.rir~~School o/ Medicine. Depur/nlcnl of Psychialry. Depression Research Unit: Myrna M. Weissman, Ph.D.: .-tssociate Prolextor. k’ale Cjniversitx School of Medicine, Department 01 Psychiatry. Deprecsion Research Unit: Janis Tanner. B.A.: Pro,qrammer. k,ale Universily School 01‘ Medicinr, Department of Psychiatry, Depression Rc.vearch Uni/; Julian Lieb, M.B., B.Ch.: Assistant Pro/Ps.sor. Yale C’niver.ritv School o/ Medic,int,, DL,parmmenf of P.swhiatrv Supported in part bv agrantjrom CIBA-Geig_v Corp. Reprint requests should be addressed 10 Brigitte A. Prusoj: M.P.H., Yale University School oJ Medicine. Department of Psvchiatrv. Depression Research Unit. 904 Howard Avenue. Suite 2.4. ,Vc,rt Haven. Cow. 06520. fc)1976 bv Grune & Stratton. Inc.
Comprehensive PsychiaWy.Vol. 17. No. 6 (November/December).
1976
749
750
PRUSOFF
Table 1. Symptoms Factor
I
in Hamilton Factor II
Sleep Dtsturbance
Somatzatw3n
Factors and Additional Factor Ill
Symptoms
in Total Score Only
Factor IV
Anxiety-Depressmn
Apathy
ET AL.
Total Score AdditIonal
Symptoms
Insomnia--early
Anxiety-somatic
Depressed mood
Work and actwities
Loss of weight
Insomnia-mtddle
Somatic symptoms-
Feehngs of guilt
Retardatwn
Durnal
variation
g+troinrestinal Insomnia-late
Somatic
symptoms-
Swcide
Depersonalizatmn
Genital symptoms
Agitation
Paranoid symptoms
Hypochondrws
Anxwty-psychic
Obsewonal
general
and detealiration
compulswe
and wnpfoms
Treatment All patients were treated on an outpatient basis. The study was double-blind, with patients randomly assigned to treatment. Each tablet of maprotiline contained 37.5 mg, and each tablet of amitriptyline contained 25 mg of medication. The dose for the first 3 days was fixed at 3 tablets per day and at 4 tablets per day for the next 4 days. The balance of the study was conducted in a flexible dose format between 4 and 8 tablets per day.
Assessment
Measures
Assessments were made at the initial evaluation, at day 3, and at weekly intervals for 4 weeks thereafter. As 25% of the patients missed the day 3 interview, it is not included in this analysis. The major outcome measure was manifest psychopathology as rated by the treating psychiatrist on the Hamilton Rating Scale for Depression.’ The Hamilton Rating Scale includes 20 individual symptoms comprising a total score, which is the sum of the 20 symptoms and 4 factors as reported by the Early Clinical Drug Evaluation UniL5 The factors are shown in Table I. Normally, “insight” is an additional symptom in the Hamilton Rating Scale. Since it was not found in any of the patients in this study, it did not affect the factor
Statistical
scores.
Analysis
In order to examine the different response rates of the two drugs over the 4-week treatment period, an analysis of variance for repeated measures was used.” For the five ratings (pretreatment and 4 weekly ratings), time trends were calculated by use of orthogonal components. In order to examine the relative speed with which the five factor scores were altered (i.e., the shape of the curve over time), the data were analyzed for linear, quadratic, and residual nonlinear trends and tested for statistical significance with the F test. A significant positive linear component indicates a curve with overall continued reduction in symptomatology over time; a significant quadratic component indicates a curve with a curvilinear function, wherein the changes noted are either prominent early in time and minimal later, or vice versa. The remaining residual nonlinear trends are the pooled third and fourth powers of the equation and explain further trends in nonlinearity. A significant interaction between drug groups and trend components indicates that response curves differ between amitriptyline and maprotiline. For a repeated measure analysis, each subject must have a complete factorial structure with no missing observations. Therefore, the analysis was restricted to those patients who completed 4 weeks of treatment. An isolated missed visit, other than the last visit, was not grounds for exclusion for that patient, but the missed rating was extrapolated by averaging the rating prior to the missed visit with the subsequent rating. The full sample entering the study consisted of 84 patients. Sixty patients completed 4 weeks of treatment. In addition to the 24 early terminators, 9 more patients were excluded from the statistical analysis because they were found either to use additional psychotropic medication or they did not maintain an adequate dose of study medication. An adequate dose of medication was defined as an average of 75% or more of the minimum daily dose stipulated. The final sample for the statistical analysis consisted of a subsample of 51 patients, of which 27 were on maprotiline and 24 on amitriptyline.
of Varlatlon
07
10.9;
3.0
2
2
Time (residual nonlInear)
Time (R) x drug group
Error
001.
.Ol.
( MS, mean square.
fp;
pr
05
20
49
1.3
00
Time 1Q) x drug group
96
25 6
1
1
Time (quadrawl
Error
1.9
49
Error
1 19.5
1
1
4.1 4.6
Time (Itnear)
‘PC
t
1
49
WI
Time (L) x drug group
Drug groups Error Wlthin Subjects
Between Subjects
Source
2.3
8.5:
0.0
12.9t
12
01
73
37
2.1
17.1
4.5
0.2
190.6
63 2:
MS1
8.4 180
0.4
Measures
01
6 It
0.6
4 7’
00
41 7:
0.5
4.5
4.6
25 6
5.1
3.1
76.3
38
33
372 4
17.2
3.1
10
5 6t
0.6
14.9:
09
98 3:
02
test
te*t MSll
F
0 64
0 02
0 18
09
17
7.5
1.1
4.7
1169
4.5
0.0
MS(
Apathy
Factors and Total Score
A~ety-Depre~~~~n
on Hamilton
F
Somatuatkw
for Repeated
0.9
test
F
Sleep Dlsturbance
Table 2. Analysis of Variance
0.0
03
19
8.3t
4.1’
102 81
0.0
test
F
15.9
25.9
162 5
29 5
22
826.8
29.7
30.8
4417.5
137.8
1.1
MW
F
00
tes
18
10 2 i
0.1
280:
1 .o
148 Si_
Total Score
PAUSOFF
752
Sleep
disturbance
ET AL.
Somatization
Apathy
Significant (p
Oh+-%--&
I Weeks
of
2
3
4
treotment
Fig. 1. Change over time in Hamilton factor ratings in depressed patients treated with maprotiline (N = 27) and amitriptyline (N = 24).
RESULTS
The results of the analysis of variance with repeated measures for the four Hamilton factors and the total score are shown in Table 2. There are no significant differences between the two drug groups when the weekly ratings are averaged over the 4 weeks of treatment. This is shown in the first line of Table 2 as the “between subject” effect for drug groups. The time trends and their interactions are tested in the “within subject” part of the table. All five scores have significant linear and quadratic time trend components and, except for the “apathy” factor, a further nonlinear residual effect. As can be seen, there are significant curvilinear reductions in symptomatology over the 4-week period in all factors of psychopathology. A significant interaction component between time and drug groups indicates differences in response rates between amitriptyline and maprotiline. Only one significant interaction is shown in Table 2. A significant time (linear) x drug group interaction in the apathy factor is illustrated in Fig. 1. Symptom reduction in the apathy factor is greater in maprotiline than in amitriptyline. When the two symptoms (“work and interest” and “retardation”) in this factor were analyzed separately by drug it was the “work and interest” items that showed statistical significance. The same pattern of response could be seen in “retardation,” but because the general level of pathology for this item was low, it did not reach statistical significance by itself. Figure 1 shows the response curves over time in the maprotiline and amitriptyline groups for the Hamilton factors. The significant quadratic component in the repeated measurement analysis was clearly due to the rapid reduction in pathology during the first week of treatment. In all factors, the greatest reduction
AMITRIPTYLINE
AND
MAPROTILINE
ANALYSIS
in pathology occurred in the first week of treatment. this reduction less than 50% in the first week.
753
Only in the apathy factor was
DISCUSSION
Both maprotiline and amitriptyline were effective in reducing symptoms of depression in acutely depressed, predominantly neurotic outpatients. The pattern and rate of change was similar in both drugs. The greatest proportion of change occurred in the first week of treatment with further, more gradual change in the remaining 3 weeks. The only significant difference between the two drugs was that the response slope of maprotiline was steeper than that of amitriptyline in the apathy factor, i.e., maprotiline, as compared to amitriptyline, produced more amelioration of patient apathy. These results, however, require replication before any conclusion can be drawn. An isolated finding such as this might easily be dismissed as due to chance expectation or artifact. The pretreatment pathology level, by chance, was higher on the apathy factor in patients receiving maprotiline. This can result in a statistical artifact commonly called “regression toward the mean,” which results in posttreatment scores being lower in higher pretreatment scores, and higher in the case of lower pretreatment scores.’ Moreover, it must be pointed out that 40% of the original sample dropped out prior to the end of the 4-week trial and could not be included in a statistical analysis that measured rates of change. The resulting sample may differ substantially from the original cohort and lead to biased conclusions about the relative efficacy of the two drugs. Nevertheless, the finding is interesting because, prior to commencing the double-blind trials, it had been hypothesized that maprotiline would be more effective in these symptoms included in the apathy factor, and this is precisely the effect that was found in the present study. If this finding is upheld in other studies of maprotiline, it would have several important implications. Psychotic patients usually score high on the apathy factor. Haskell et al.” have shown in an open trial of amitriptyline that psychotic, as contrasted with neurotic, depressives responded more slowly to treatment in the first 4 weeks. If maprotiline is more effective in reducing apathy, it could have therapeutic value for the psychotically depressed patients. The diagnosis of psychotic depression, however, is infrequent in outpatient depressives (i.e., only 11% received that diagnosis in this study). However, subtypes of depression recently developed within the wider spectrum of depressive neurosis may be more useful in further studies evaluating subtle differences between amitriptyline and maprotiline.“,“’ CONCLUSION
A comparison of maprotiline and amitriptyline in the treatment of acutely depressed outpatients who completed 4 weeks of treatment found similar rates and patterns of change in the symptoms of depression, with the greatest reduction in psychopathology occurring during the first week of treatment. There was one significant difference between maprotiline and amitriptyline in their rate of response and pattern of symptom reduction. Maprotiline shows a significantly greater reduction in apathy, which is interesting because it is the
754
PRUSOFF
ET AL.
difference that had been predicted, based on results of animal studies and open trials. These findings need to be replicated with larger and different patient samples before a conclusion can be drawn. There have been a number of double-blind clinical trials comparing maprotiline with a conventional tricyclic, both in the United States and in other countries. None of these noted the difference in the reduction of apathy.2 However, none of the studies used the repeated measurement analysis, with the exception of Amin et al.,’ where only five patients in each drug group were included in the analysis. It might be worthwhile to reexamine the results of other studies of maprotiline using pooled data in a repeated measurement analysis. If such replications are undertaken, it might also be useful to stratify by type of depression, since the improvement on apathy noted in patients on maprotiline could have therapeutic implications in depressions where apathy and loss of interest are prominent features. ACKNOWLEDGMENT Appreciation is expressed to Dr. Eugene S. Paykel for initiating the study. REFERENCES 1. Amin M, Brahm E, Bronheim LL, et al: A double-blind, comparative clinical trial with Ludiomil (CIBA 34, 276-Ba) and amitriptyline in newly admitted depressed patients. Curr Ther Res 15:691-699, 1973 2. Weissman MM, Lieb J, Prusoff B, et al: A double-blind trial of maprotiline (Ludiomil) and amitriptyline in depressed outpatients. Acta Psychiatr Stand 52:225-236, 1975 3. Raskin A, Schulterbrandt J, Reatig N, et al: Factors of psychopathology in interview, ward behavior, and self report ratings of hospitalized depressives. J Consult Psycho1 31:270-278, I967 4. Hamilton M: A rating scale for depression. J Neural Neurosurg Psychiatry 23:56-62, 1960 5. Guy W, Bonato R: E.C.D.E.U. Assessment Battery, Second Revision. U.S. DHEW, PHS, HSMA, NIMH, Chevy Chase, Md, 1970.
6. Health Science Computing Facility BMD P2V: Repeated Measures Analysis of Variance and Covariance. University of California, revised June 1974 A: How 7. Campbell PT, Erlebacher regression artifacts in quasi-experimental evaluations can mistakenly make compensatory education look harmful. Disadvant Child 3:165-210, 1970 8. Haskell DS, DiMascio A, Prusoff B: Rapidity of symptom reduction in depressions treated with amitriptyline. J Nerv Ment Dis 160:2433, 1975 9. Klein DF: Endogenomorphic depression. Arch Gen Psychiatry 31:4477454, 1974 10. Paykel ES: Classification of depressed patients: A cluster analysis derived grouping. Br J Psychiatry 118:275-288, 1971
A. Prusoff,
Myrna
M. Weissman,
Janis Tanner.
and Julian
Lieb
P
maprotiline RELIMINARY open-labeled studies ’ had characterized (LudiomiP) as a tetracyclic antidepressant that enhanced both mood and drive, reduced the symptoms of agitation and retardation, and had a fast onset of action. These effects might appear in patients as an increased interest in the environment and decreased apathy during the initial weeks of treatment. To test this observation, maprotiline was compared to amitriptyline hydrochloride (ElaviP ), a conventional tricyclic, in a 4-week double-blind clinical trial with outpatient depressives. No difference between these two compounds in timing of response, efficacy, or side effects was shown after 1 week of treatment or at the completion of the triaL2 when utilizing a standard analysis of covariance. Using a repeated measurement analysis, we then examined the differences in rates of change between the drugs. Since the repeated measurement analysis uses the total period of observation instead of discrete points in time, it may be more sensitive to detecting those differences that were hypothesized prior to initiating the study. This paper will demonstrate the use of repeated measurement analysis to compare rates, pattern, and timing of symptom change between maprotiline and amitriptyline over the 4 weeks of treatment.
MATERIALS
AND
METHODS
Subjects Subjects were between the ages of 21 and 65 (mean age of 36). exhibiting a primary depressive disorder that reached a score of at least 7 on the Raskin Three-Area Scale (range 3- 15). which measures verbal report, behavior, and secondary symptoms of depression..’ A majority of patients (89%) were given a diagnosis of depressive neurosis; the remaining few patients were diagnosed as psychotic depression. Full details of the sample and criteria for selection and exclusion have been described elsewhereP
From the Yale University School of Medicine, Departmenr of Pspchiatr~. Depression Research Unit, New Haven, Corm. Brigitte A. Prusoff. M.P.H.: ,4ssistanl ProJe~sor, Yale l’nivrr.rir~~School o/ Medicine. Depur/nlcnl of Psychialry. Depression Research Unit: Myrna M. Weissman, Ph.D.: .-tssociate Prolextor. k’ale Cjniversitx School of Medicine, Department 01 Psychiatry. Deprecsion Research Unit: Janis Tanner. B.A.: Pro,qrammer. k,ale Universily School 01‘ Medicinr, Department of Psychiatry, Depression Rc.vearch Uni/; Julian Lieb, M.B., B.Ch.: Assistant Pro/Ps.sor. Yale C’niver.ritv School o/ Medic,int,, DL,parmmenf of P.swhiatrv Supported in part bv agrantjrom CIBA-Geig_v Corp. Reprint requests should be addressed 10 Brigitte A. Prusoj: M.P.H., Yale University School oJ Medicine. Department of Psvchiatrv. Depression Research Unit. 904 Howard Avenue. Suite 2.4. ,Vc,rt Haven. Cow. 06520. fc)1976 bv Grune & Stratton. Inc.
Comprehensive PsychiaWy.Vol. 17. No. 6 (November/December).
1976
749
750
PRUSOFF
Table 1. Symptoms Factor
I
in Hamilton Factor II
Sleep Dtsturbance
Somatzatw3n
Factors and Additional Factor Ill
Symptoms
in Total Score Only
Factor IV
Anxiety-Depressmn
Apathy
ET AL.
Total Score AdditIonal
Symptoms
Insomnia--early
Anxiety-somatic
Depressed mood
Work and actwities
Loss of weight
Insomnia-mtddle
Somatic symptoms-
Feehngs of guilt
Retardatwn
Durnal
variation
g+troinrestinal Insomnia-late
Somatic
symptoms-
Swcide
Depersonalizatmn
Genital symptoms
Agitation
Paranoid symptoms
Hypochondrws
Anxwty-psychic
Obsewonal
general
and detealiration
compulswe
and wnpfoms
Treatment All patients were treated on an outpatient basis. The study was double-blind, with patients randomly assigned to treatment. Each tablet of maprotiline contained 37.5 mg, and each tablet of amitriptyline contained 25 mg of medication. The dose for the first 3 days was fixed at 3 tablets per day and at 4 tablets per day for the next 4 days. The balance of the study was conducted in a flexible dose format between 4 and 8 tablets per day.
Assessment
Measures
Assessments were made at the initial evaluation, at day 3, and at weekly intervals for 4 weeks thereafter. As 25% of the patients missed the day 3 interview, it is not included in this analysis. The major outcome measure was manifest psychopathology as rated by the treating psychiatrist on the Hamilton Rating Scale for Depression.’ The Hamilton Rating Scale includes 20 individual symptoms comprising a total score, which is the sum of the 20 symptoms and 4 factors as reported by the Early Clinical Drug Evaluation UniL5 The factors are shown in Table I. Normally, “insight” is an additional symptom in the Hamilton Rating Scale. Since it was not found in any of the patients in this study, it did not affect the factor
Statistical
scores.
Analysis
In order to examine the different response rates of the two drugs over the 4-week treatment period, an analysis of variance for repeated measures was used.” For the five ratings (pretreatment and 4 weekly ratings), time trends were calculated by use of orthogonal components. In order to examine the relative speed with which the five factor scores were altered (i.e., the shape of the curve over time), the data were analyzed for linear, quadratic, and residual nonlinear trends and tested for statistical significance with the F test. A significant positive linear component indicates a curve with overall continued reduction in symptomatology over time; a significant quadratic component indicates a curve with a curvilinear function, wherein the changes noted are either prominent early in time and minimal later, or vice versa. The remaining residual nonlinear trends are the pooled third and fourth powers of the equation and explain further trends in nonlinearity. A significant interaction between drug groups and trend components indicates that response curves differ between amitriptyline and maprotiline. For a repeated measure analysis, each subject must have a complete factorial structure with no missing observations. Therefore, the analysis was restricted to those patients who completed 4 weeks of treatment. An isolated missed visit, other than the last visit, was not grounds for exclusion for that patient, but the missed rating was extrapolated by averaging the rating prior to the missed visit with the subsequent rating. The full sample entering the study consisted of 84 patients. Sixty patients completed 4 weeks of treatment. In addition to the 24 early terminators, 9 more patients were excluded from the statistical analysis because they were found either to use additional psychotropic medication or they did not maintain an adequate dose of study medication. An adequate dose of medication was defined as an average of 75% or more of the minimum daily dose stipulated. The final sample for the statistical analysis consisted of a subsample of 51 patients, of which 27 were on maprotiline and 24 on amitriptyline.
of Varlatlon
07
10.9;
3.0
2
2
Time (residual nonlInear)
Time (R) x drug group
Error
001.
.Ol.
( MS, mean square.
fp;
pr
05
20
49
1.3
00
Time 1Q) x drug group
96
25 6
1
1
Time (quadrawl
Error
1.9
49
Error
1 19.5
1
1
4.1 4.6
Time (Itnear)
‘PC
t
1
49
WI
Time (L) x drug group
Drug groups Error Wlthin Subjects
Between Subjects
Source
2.3
8.5:
0.0
12.9t
12
01
73
37
2.1
17.1
4.5
0.2
190.6
63 2:
MS1
8.4 180
0.4
Measures
01
6 It
0.6
4 7’
00
41 7:
0.5
4.5
4.6
25 6
5.1
3.1
76.3
38
33
372 4
17.2
3.1
10
5 6t
0.6
14.9:
09
98 3:
02
test
te*t MSll
F
0 64
0 02
0 18
09
17
7.5
1.1
4.7
1169
4.5
0.0
MS(
Apathy
Factors and Total Score
A~ety-Depre~~~~n
on Hamilton
F
Somatuatkw
for Repeated
0.9
test
F
Sleep Dlsturbance
Table 2. Analysis of Variance
0.0
03
19
8.3t
4.1’
102 81
0.0
test
F
15.9
25.9
162 5
29 5
22
826.8
29.7
30.8
4417.5
137.8
1.1
MW
F
00
tes
18
10 2 i
0.1
280:
1 .o
148 Si_
Total Score
PAUSOFF
752
Sleep
disturbance
ET AL.
Somatization
Apathy
Significant (p
Oh+-%--&
I Weeks
of
2
3
4
treotment
Fig. 1. Change over time in Hamilton factor ratings in depressed patients treated with maprotiline (N = 27) and amitriptyline (N = 24).
RESULTS
The results of the analysis of variance with repeated measures for the four Hamilton factors and the total score are shown in Table 2. There are no significant differences between the two drug groups when the weekly ratings are averaged over the 4 weeks of treatment. This is shown in the first line of Table 2 as the “between subject” effect for drug groups. The time trends and their interactions are tested in the “within subject” part of the table. All five scores have significant linear and quadratic time trend components and, except for the “apathy” factor, a further nonlinear residual effect. As can be seen, there are significant curvilinear reductions in symptomatology over the 4-week period in all factors of psychopathology. A significant interaction component between time and drug groups indicates differences in response rates between amitriptyline and maprotiline. Only one significant interaction is shown in Table 2. A significant time (linear) x drug group interaction in the apathy factor is illustrated in Fig. 1. Symptom reduction in the apathy factor is greater in maprotiline than in amitriptyline. When the two symptoms (“work and interest” and “retardation”) in this factor were analyzed separately by drug it was the “work and interest” items that showed statistical significance. The same pattern of response could be seen in “retardation,” but because the general level of pathology for this item was low, it did not reach statistical significance by itself. Figure 1 shows the response curves over time in the maprotiline and amitriptyline groups for the Hamilton factors. The significant quadratic component in the repeated measurement analysis was clearly due to the rapid reduction in pathology during the first week of treatment. In all factors, the greatest reduction
AMITRIPTYLINE
AND
MAPROTILINE
ANALYSIS
in pathology occurred in the first week of treatment. this reduction less than 50% in the first week.
753
Only in the apathy factor was
DISCUSSION
Both maprotiline and amitriptyline were effective in reducing symptoms of depression in acutely depressed, predominantly neurotic outpatients. The pattern and rate of change was similar in both drugs. The greatest proportion of change occurred in the first week of treatment with further, more gradual change in the remaining 3 weeks. The only significant difference between the two drugs was that the response slope of maprotiline was steeper than that of amitriptyline in the apathy factor, i.e., maprotiline, as compared to amitriptyline, produced more amelioration of patient apathy. These results, however, require replication before any conclusion can be drawn. An isolated finding such as this might easily be dismissed as due to chance expectation or artifact. The pretreatment pathology level, by chance, was higher on the apathy factor in patients receiving maprotiline. This can result in a statistical artifact commonly called “regression toward the mean,” which results in posttreatment scores being lower in higher pretreatment scores, and higher in the case of lower pretreatment scores.’ Moreover, it must be pointed out that 40% of the original sample dropped out prior to the end of the 4-week trial and could not be included in a statistical analysis that measured rates of change. The resulting sample may differ substantially from the original cohort and lead to biased conclusions about the relative efficacy of the two drugs. Nevertheless, the finding is interesting because, prior to commencing the double-blind trials, it had been hypothesized that maprotiline would be more effective in these symptoms included in the apathy factor, and this is precisely the effect that was found in the present study. If this finding is upheld in other studies of maprotiline, it would have several important implications. Psychotic patients usually score high on the apathy factor. Haskell et al.” have shown in an open trial of amitriptyline that psychotic, as contrasted with neurotic, depressives responded more slowly to treatment in the first 4 weeks. If maprotiline is more effective in reducing apathy, it could have therapeutic value for the psychotically depressed patients. The diagnosis of psychotic depression, however, is infrequent in outpatient depressives (i.e., only 11% received that diagnosis in this study). However, subtypes of depression recently developed within the wider spectrum of depressive neurosis may be more useful in further studies evaluating subtle differences between amitriptyline and maprotiline.“,“’ CONCLUSION
A comparison of maprotiline and amitriptyline in the treatment of acutely depressed outpatients who completed 4 weeks of treatment found similar rates and patterns of change in the symptoms of depression, with the greatest reduction in psychopathology occurring during the first week of treatment. There was one significant difference between maprotiline and amitriptyline in their rate of response and pattern of symptom reduction. Maprotiline shows a significantly greater reduction in apathy, which is interesting because it is the
754
PRUSOFF
ET AL.
difference that had been predicted, based on results of animal studies and open trials. These findings need to be replicated with larger and different patient samples before a conclusion can be drawn. There have been a number of double-blind clinical trials comparing maprotiline with a conventional tricyclic, both in the United States and in other countries. None of these noted the difference in the reduction of apathy.2 However, none of the studies used the repeated measurement analysis, with the exception of Amin et al.,’ where only five patients in each drug group were included in the analysis. It might be worthwhile to reexamine the results of other studies of maprotiline using pooled data in a repeated measurement analysis. If such replications are undertaken, it might also be useful to stratify by type of depression, since the improvement on apathy noted in patients on maprotiline could have therapeutic implications in depressions where apathy and loss of interest are prominent features. ACKNOWLEDGMENT Appreciation is expressed to Dr. Eugene S. Paykel for initiating the study. REFERENCES 1. Amin M, Brahm E, Bronheim LL, et al: A double-blind, comparative clinical trial with Ludiomil (CIBA 34, 276-Ba) and amitriptyline in newly admitted depressed patients. Curr Ther Res 15:691-699, 1973 2. Weissman MM, Lieb J, Prusoff B, et al: A double-blind trial of maprotiline (Ludiomil) and amitriptyline in depressed outpatients. Acta Psychiatr Stand 52:225-236, 1975 3. Raskin A, Schulterbrandt J, Reatig N, et al: Factors of psychopathology in interview, ward behavior, and self report ratings of hospitalized depressives. J Consult Psycho1 31:270-278, I967 4. Hamilton M: A rating scale for depression. J Neural Neurosurg Psychiatry 23:56-62, 1960 5. Guy W, Bonato R: E.C.D.E.U. Assessment Battery, Second Revision. U.S. DHEW, PHS, HSMA, NIMH, Chevy Chase, Md, 1970.
6. Health Science Computing Facility BMD P2V: Repeated Measures Analysis of Variance and Covariance. University of California, revised June 1974 A: How 7. Campbell PT, Erlebacher regression artifacts in quasi-experimental evaluations can mistakenly make compensatory education look harmful. Disadvant Child 3:165-210, 1970 8. Haskell DS, DiMascio A, Prusoff B: Rapidity of symptom reduction in depressions treated with amitriptyline. J Nerv Ment Dis 160:2433, 1975 9. Klein DF: Endogenomorphic depression. Arch Gen Psychiatry 31:4477454, 1974 10. Paykel ES: Classification of depressed patients: A cluster analysis derived grouping. Br J Psychiatry 118:275-288, 1971