A Comparison of Antidepressant Medications in Neurotic and Psychotic Patients J. Richard
Wittenborn, PhD, Nafi Kiremitci, MD
\s=b\ The responses of 225 newly hospitalized depressed women to amitriptyline hydrochloride, imipramine hydrochloride, and thioridazine were compared with particular reference to the psychotic-neurotic distinction. During the first week, more psychotic patients required sedation and more antidepressant medication than did neurotic patients. All treatment groups showed improvement in psychometric criteria after the first week. There was decreasing improvement
through the successive weeks, and no statistically significant differences among treatments emerged. Responses of the neurotic group were superior to those of the psychotic group, but there was no psychometric evidence of interaction between diagnostic classification and treatment effect. The results do not support the hypothesis that any one of these treatments is prefpatients or for psychotic patients. (Arch Gen Psychiatry 32:1172-1176, 1975)
erable for neurotic
efficacy analysis explores the medications (amitriptyline hydrochloride, Theof presenthydrochloride, thioridazine) relative
three
and is orga¬ and nized from the standpoint of three major questions: 1. Do these medications differ from each other with re¬ spect to the degree to which various manifestations of de¬
imipramine
pression respond? 2. Do patients with psychotic depressions respond
to
different from that of patients with a neurotic depression, regardless of the treatment selected? 3. Is there evidence that the different treatments inter¬ act with a neurotic-psychotic diagnostic distinction in a way to indicate that one medication is more effective in the management of patients with psychotic depressions, while some other medication is more effective in the man¬ agement of patients with neurotic depressions? treatment in
a manner
Feb 11, 1975. Interdisciplinary Research Center, Rutgers University, New Brunswick (Dr. Wittenborn); and New Jersey State Hospital at Marlboro (Dr. Kiremitci). Reprint requests to the Interdisciplinary Research Center, Rutgers University, New Brunswick, NJ 08903 (Dr. Wittenborn).
Accepted for publication From the
SAMPLE The total sample was composed of 225 women newly admitted to the New Jersey State Hospital at Marlboro. All the patients were suffering from a depressed state that was sufficiently severe and sufficiently predominant among the complaints at admission to re¬ quire the use of antidepressant treatment. Patients under 19 or over 65 years of age, patients with a toxic or neurologic condition, patients whose current manifestations were primarily schizo¬ phrenic, or patients whose depression was a short-lived reaction were excluded. The total sample was divided into three groups: a currently psy¬ chotic group comprising 69 patients, a group comprising 113 pa¬ tients who were neurotic, and a group of 43 patients who were neither psychotic nor neurotic, and, as a consequence, were elimi¬ nated from the present analysis. The diagnostic composition of these three groups is summarized in Table 1. The psychotic group was older and had more previous hospital¬ izations than the neurotic group (Table 2). There was no differ¬ ence in education level.
METHODS The patients were assigned at random to one of the three medi¬ cations (amitriptyline, imipramine, or thioridazine) and were maintained on a double-blind regimen of treatment. No washout period was required before treatment was initiated. The respec¬ tive dosage units were 25 mg, 25 mg, and 50 mg. Six units were recommended as the standard daily dosage, but the regulation of the dosage was managed at the discretion of the psychiatrist. Be¬ cause some patients were severely depressed and treatment re¬ sistant, the recommended daily dosage of six units was frequently exceeded. Since concurrent psychotherapeutic influences may obscure dif¬ ferences in response to various psychotropics, particularly anti¬ depressants and antianxiety medications, the patients in the pres¬ ent inquiry received only enough psychiatric attention to meet the management and assessment requirements of the study. Supple¬ mentary nighttime sedative medication was prescribed for 30% of the sample during the first week of treatment. For the purpose of the present comparison, the short-term use of sedatives in the management of severe initial agitation was considered preferable to psychotherapeutic efforts that could have a persisting effect and
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Table
time the patients started medication therapy and at weekly inter¬ vals thereafter. These three independent ratings were reconciled (by using the most severe rating) on a scale-by-scale basis, and the reconciled set of ratings provided the basis for the data analy¬ sis. The weekly self-report inventories (the Zung self-rating de¬ pression scale and the items from the Minnesota Multiphasic Per¬ sonality Inventory required for the psychasthenia and the depression scores) were prepared by the patients under the psy¬ chologist's supervision. The Zung inventory was scored on the basis of prior factor analyses of the Rutgers-M ari boro data and provided both a positive and a negative mood assessment. A weekly treatment log for each patient included a record of all medication and was used in the present analysis to identify pa¬ tients who had required sedation, who had required more assigned medication than the recommended dosage, and for whom the scheduled treatment was terminated early.
1.—Diagnostic Composition of Sample of 225 Depressed Women
Depressed Psychotic State =
Depressed Neurotic N
69
Psychotic
depressive reaction
113
neurosis
72
depressive
Psychoneurotic
35
depressive
Schizoid
(secondary) Schizophrenic (secondary)
=
Depressive
State not Psychotic nor Neurotic = 43 Involutional 21 Manic-
18
reaction
25
depressed
Alcoholic
(secondary) Depressive
Paranoid
(secondary)
12
Manic-
depressive circular
10
reaction
Depressive
situational
adjustment
Involutional
(secondary)
Alcoholic
(secondary)
RESULTS
during subsequent weeks.
could obscure differences
During the first week of treatment, 56 (30%) of the 182 patients involved in the present comparison received nighttime sedation. Of the 58 persons in the imipramine group, 26 (45%) required sedation, while only 11 (20%) of the 56 persons in the thioridazine group required sedation. This is a statistically significant contrast (P=.05). The need for sedation in the amitriptyline group was inter¬ mediate and did not contrast significantly with the thio¬
Assessments
The long form of the Wittenborn Psychiatric Rating Scales (WPRS) was used as a part of the comprehensive pretreatment assessment of all patients.1 The raw factor scores (based on the average of the ratings for the scales comprising that factor) are relatively sensitive, and small intergroup differences can be statis¬ tically significant. This is illustrated in Table 2, which discloses that in terms of raw factor scores, the psychotic sample was more heavily burdened with symptoms than was the neurotic sample. In order to facilitate intersymptom comparisons, the raw scores can be expressed in terms of standard scores that range from 1 to 10. The standard scores show both samples to be characterized by a relatively high order of anxiety, depression, and obsessive-com¬ pulsive qualities. The WPRS short form symptom ratings were made by the psy¬ chiatrist, the psychologist, and the nurse, independently at the '
ridazine group. Of the 113 neurotic patients, 29 (26%) required night¬ time sedation. Among the 69 psychotic patients, 27 (39%) required nighttime sedation. When the chi-square test was applied, this difference was barely significant at the .05 level and presumably reflects the greater disturbance of the psychotic group. Forty-seven percent of the patients in the psychotic
Table 2.—Pretreatment Contrasts Between
Depressed
Psychotic (N
WPRS Factors*
Anxiety Hysterical conversion Manic state Depressive total Obstructive subscore
Apathy subscore Withdrawal subscore Flatness subscore Schizophrenic excitement
Psychotic belligerence Paranoia
Hebephrenia Compulsive-obsessive Intellectual impairment Homosexual dominance Ideas of grandeur
Demographic data Age,
yr
Educationf Previous Hospitalizations *
Raw Score X 1.20 0.80 0.27 1.12 0.32
=
and Neurotic
Diagnostic Groups Depressed
Neurotic
69) Standard Score
1.33 1.57 0.74 0.38 0.19 0.40
0.35 0.92 0.26 0.23 0.04 X 39.88 3.72 2.33
Wittenborn Psychiatric Rating Scales is indicated by WPRS. was used to compute average education:
t An arbitrary scale pletion of grade 8, 2.
Psychotic
X
(N
=
113)
Raw Score X
Standard Score X
t
1.28 0.72 2.01 3.77 2.31 4.19 2.63 3.41 4.41 0.13 4.82 2.28 2.27 2.94 0.52 0.26
1.10 0.90 0.33 0.84 0.17 0.97 1.25 0.54 0.24 0.19 0.13 0.29 0.76 0.15 0.24 0.04 X 35.43 3.87 1.51
completion of high school indicated by 4;
Raw Score
2.53 0.66 2.47 some
high school, 3; and
com¬
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Table
Mean
3.—Adjusted
Ratings for Week 3 Scores From WPRS Short Form* Treatment Group Means (Raw Score) Adjusted for Pretreatment Differences
WPRS Short Form Score
Anxiety
Depressed
Amitriptyline Hydrochloride
Diagnostic
Imipramine Hydrochloride
X X Neurotic 0.90 0.87 0.73 0.83 Psychotic Combined sample 0.84 0.86 Multifactor Covariance Analysis: = NS Treatment differences = NS Diagnostic differences = NS Diagnosis X treatment interaction Neurotic 0.65 0.64 0.80 0.71 Psychotic Combined sample 0.69 0.69
Grouping
Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction
Obsessive-compulsive
Neurotic
Psychotic
Combined sample
Somatic
0.35 0.52
Diagnostic differences Diagnosis X treatment interaction Paranoia
Neurotic
Psychotic
Combined sample
0.06 0.14 0.08
Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction
Excited
Neurotic
0.27 0.53
Psychotic
Combined sample
0.38 Multifactor Covariance Analysis: differences Treatment Diagnostic differences Diagnosis X treatment interaction
'
Combined Sample X
0.83
0.87 0.86
0.99 0.90
0.82 1.05 0.86
0.69 0.87
0.36 0.45
0.35
0.37 0.47 0.43
NS NS NS 0.40 0.32 0.36
0.48 0.54 0.45
0.45 0.40
0.06 0.05 0.05
0.08 0.10
0.34 0.55 0.42
0.29 0.49
=
= =
NS .07 NS
0.37 0.28
0.41 Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction Neurotic 0.48 0.37 Psychotic Combined sample 0.42 Multifactor Covariance Analysis: Treatment differences
Thioridazine X
=
=
—
NS NS = NS 0.11 =
=
0.12 0.08
=
—
=
NS NS NS
0.29 0.34 0.33 =
=
=
NS .01 NS
Wittenborn Psychiatric Rating Scales indicated by WPRS.
group received more than the recommended dosage dur¬ ing the third week, while only 28% of the neurotic group received more than was recommended. This contrast is statistically significant (P .05) and reflects the treat¬ ment-resistant nature of the symptoms in the psychotic group. In the thioridazine group, more psychotic than neu¬ rotic patients required increased medication, while in the imipramine group more neurotic than psychotic patients required increased medication. About 15% of the 182 patients left the project before the fourth week, but this factor did not distinguish between treatment groups or between diagnostic groups. About 7% of the patients responded to the assigned medication in an unsatisfactory manner and were reassigned to a different medication. This factor did not distinguish among treat¬ ment groups or between diagnostic groups and did not disclose an interaction between diagnosis and treatment. During the successive weeks of treatment, the diminu¬ tion in the various criteria of depression followed a typical decay curve with the greatest drop at the end of the first =
week of treatment and decreasing drops in the various cri¬ terion scores during the successive weeks. This is illus¬ trated in the Figure for the depression score from the WPRS short form; for all treatments, the reduction in se¬ verity was statistically significant by the end of the first week, and no appreciable average reduction occurred after the third week. The covariance analyses summarized in Tables 3 and 4
may be regarded as two-way factorial analyses of week 3 that have been corrected for pretreatment differ¬ ences. The significance of the difference between the cor¬ rected week 3 averages for the medication groups is perti¬ nent to question 1, the significance of the difference between the corrected week 3 averages for the neurotic group and the psychotic group is pertinent to question 2, and the significance of the interaction between treatment scores
(amitriptyline, imipramine, thioridazine) and diagnosis (psychotic vs neurotic) is pertinent to question 3. On the average, the three treatments were equally effi¬ cacious in controlling the present set of depressive mani-
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Table
4.—Adjusted
Mean
Ratings for Week 3 Self-Report Scores* Treatment Group Means (Raw Score) Adjusted for Pretreatment Differences
Self-Report
Criterion Score
MMPI-depression
Amitriptyline
Diagnostic
Hydrochloride
Grouping
X
Neurotic
Psychotic
Combined
MMPI-psychasthenia
sample
Imipramine Hydrochloride X
0.32
0.36
0.39 0.35
0.33 0.37
Multifactor Covariance Analysis:
Treatment differences
=
Diagnostic differences Diagnosis X treatment interaction
=
Neurotic
0.37 0.41
Psychotic
Combined sample
Zung-positive
NS NS 0.41
0.33 0.40
0.38
= = =
2.74
Neurotic
Combined
Sample
X
0.34 0.37
0.40 0.48 0.43
0.39 0.38
2.77
2.71 2.51
NS NS NS
2.65 2.74 2.66 Combined sample 2.74 2.66 Multifactor Covariance Analysis: Treatment differences NS = NS Diagnostic differences = NS Diagnosis X treatment interaction 1.71 Neurotic 1.67 1.76 1.95 Psychotic Combined sample 1.78 1.80 Multifactor Covariance Analysis: = NS Treatment differences = Diagnostic differences .01 = NS Diagnosis X treatment interaction
Psychotic
X 0.35 0.39 0.37
NS
—
Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction
Thioridazine
2.22 2.54
—
Zung-negative
1.68 2.05 1.83
1.69 1.86
"Minnesota Multiphasic Personality Inventory indicated by MMPI.
festations in our sample of severely depressed women. With respect to the neurotic-psychotic distinction, the neurotic patients responded better than did the psychotic patients on three criteria: symptoms of depression (P .07), symptoms of excitement (P= .01), and the nega¬ tive self-description of the Zung scale (P .01). The possi¬ bility that the class of drug could be related to diagnostic classification is of great clinical interest. In the present sample, the interactions required to support this possi¬ =
=
bility
were
not
significant.
COMMENT In the 1974
Physicians' Desk Reference,4· thiordazine indicated for patients with neurotic depressive reac¬ tions. Among patients treated with thioridazine, the pres¬ ent results show the depression, the excitement, and the Zung negative scores to be more responsive among neu¬ rotic than among psychotic patients. The indications for amitriptyline and for imipramine in the 1974 Physicians' Desk Reference emphasize endoge¬ nous depressions with no mention of neurotic depressions. The present study did not identify an endogenous group, but the results provide some indications that the neurotic patients, regardless of treatment, respond more advanta¬ geously than the psychotic patients. Certainly, there is no evidence that the assignment of any one of these medica¬ was
tions is disadvantageous for neurotic depressed patients. The relative merit of tricyclic medications and pheno¬ thiazines has provided a topic of persisting interest to clinical psychopharmacologists. Overall et al" described
the general difference between thioridazine and imipra¬ mine as inconsequential. In a later report, Overall et al" examined within-treatment group differences in symptom severity and found that thioridazine was helpful in alle¬ viating the mood in anxious depressions but was not help¬ ful for patients with retarded depressions. In contrast, imipramine improved the mood of retarded patients. Sim¬ ilar contrasts between the tricyclic amitriptyline and the phenothiazine perphenazine were described by Hollister et al7 in a later report. Raskin et al8 examined a neuroticpsychotic distinction in a comparison of chlorpromazine, imipramine, and placebo. In their sample, which was about five years older than the present sample and in¬ cluded both male and female patients, imipramine was judged better than chlorpromazine for the psychotic pa¬ tients and worse for the neurotic patients. A comparison between these findings and the present results suggests that thioridazine might have been a more appropriate an¬ tidepressant than chlorpromazine for depressed neurotic
patients.
The results confirm the hypothesis that in depressed pa¬ tients the phenothiazine tranquilizers (eg, thioridazine) are accompanied by remissive changes similar to those changes that accompany tricyclic antidepressants (eg, amitriptyline and imipramine). The neurotic-psychotic distinction within these treatment groups was not found to qualify this general similarity, and it is proposed that other distinctions" be considered as more promising aids in the selective assignment of these alternative medica¬ tions for depressed patients. The present findings, show-
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¬
Amitriptyline Hydrochloride Ra= mipramine Hydrochloride R ¡=
o
c
o
Thioridazine R t=
«J -
co CD
-*—»
CE CD >
to CD -
.
CD
Q ro
Pretreatment
Week 1
(0
Xa xi
1.51 1.17
1.05
5.5
0.77
4.9
Week 2 0.94 0.86
xt
1.36
0.94
5.0
0.90
2/152
df 2/154 F 2.39
M 2.8
6.6 4.2
5.3
0.84
4.7
6.1
2/149 0.36
0.19
(0
Week 3 0.78 0.66 2/132 0.84
Reduction in average depressive retardation scores from Wittenborn Psychiatric Rat¬ ing Scales (short form) with scores based on mean for three component rating scales; F based on residual scores; and correlated t to show significance of change within groups.
ing that all treatment groups were remitting rapidly, with the psychotic less responsive than the neurotic pa¬ tients correspond with Rockliff's description.10 Rockliff suggests, however, that such improvements as these in a neurotic group may be spontaneous, while those patients in a psychotic group may represent a therapeutic gain. This study was supported by the Psychopharmacology Research Branch, Public Health Service
grant MH 13385,
and
was
conducted
as a
part of
a
program of collaboration between the New Jersey State Hospital at Marl¬ boro and Rutgers Interdisciplinary Research Center. Helen Maurer, MSW, Bette Kiremitci, PhD, Carol Trabalik, RN, and June Rogers, RN, participated in this study.
Nonproprietary Names and Trademarks of Drugs Amitriptyline hydrochloride-.Ë'tomi. Chlorpromazine-Cromedazine, Chlor-pz, Thorazine. Thioridazine—Mellaril.
References 1. Wittenborn JR: Symptom patterns in tients. J Consult Psychol 15:290-302, 1951. 2. Wittenborn JR: The dimensions of
134:117-128, 1962. 3. Wittenborn
a
group of mental
hospital pa-
psychosis. J Nerv
Ment Dis
individual JR, Dempster A, Maurer H, differences as potential predictors of response to pharmacology. J Nerv Ment Dis 139:186-194, 1964. 4. Physicians' Desk Reference, ed 28. Oradell, NJ, Medical Economics Co, 1974. 5. Overall JE, Hollister LE, Meyer F, et al: Imipramine and thioridazine in depressed and schizophrenic patients. JAMA 189:605-608, 1964. et al: Pretreatment
6. Overall JE, Hollister LE, Johnson M, et al: Nosology of depression and differential response to drugs. JAMA 195:946-948, 1966. 7. Hollister LE, Overall JE, Shelton J, et al: Drug therapy of depression. Arch Gen Psychiatry 17:486-493, 1967. 8. Raskin A, Schutterbrandt JG, Reatig N, et al: Differential response to chlorpromazine, imipramine, and placebo. Arch Gen Psychiatry 23:164-173, 1970. 9. Wittenborn JR, Kiremitci N, Weber ESP: The choice of alternative antidepressants. J Nerv Ment Dis 156:97-108, 1973. 10. Rockliff BW: Measurement of drug effects in newly hospitalized depressives. Dis Nerv Syst 32:532-537, 1971.
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Wittenborn, PhD, Nafi Kiremitci, MD
\s=b\ The responses of 225 newly hospitalized depressed women to amitriptyline hydrochloride, imipramine hydrochloride, and thioridazine were compared with particular reference to the psychotic-neurotic distinction. During the first week, more psychotic patients required sedation and more antidepressant medication than did neurotic patients. All treatment groups showed improvement in psychometric criteria after the first week. There was decreasing improvement
through the successive weeks, and no statistically significant differences among treatments emerged. Responses of the neurotic group were superior to those of the psychotic group, but there was no psychometric evidence of interaction between diagnostic classification and treatment effect. The results do not support the hypothesis that any one of these treatments is prefpatients or for psychotic patients. (Arch Gen Psychiatry 32:1172-1176, 1975)
erable for neurotic
efficacy analysis explores the medications (amitriptyline hydrochloride, Theof presenthydrochloride, thioridazine) relative
three
and is orga¬ and nized from the standpoint of three major questions: 1. Do these medications differ from each other with re¬ spect to the degree to which various manifestations of de¬
imipramine
pression respond? 2. Do patients with psychotic depressions respond
to
different from that of patients with a neurotic depression, regardless of the treatment selected? 3. Is there evidence that the different treatments inter¬ act with a neurotic-psychotic diagnostic distinction in a way to indicate that one medication is more effective in the management of patients with psychotic depressions, while some other medication is more effective in the man¬ agement of patients with neurotic depressions? treatment in
a manner
Feb 11, 1975. Interdisciplinary Research Center, Rutgers University, New Brunswick (Dr. Wittenborn); and New Jersey State Hospital at Marlboro (Dr. Kiremitci). Reprint requests to the Interdisciplinary Research Center, Rutgers University, New Brunswick, NJ 08903 (Dr. Wittenborn).
Accepted for publication From the
SAMPLE The total sample was composed of 225 women newly admitted to the New Jersey State Hospital at Marlboro. All the patients were suffering from a depressed state that was sufficiently severe and sufficiently predominant among the complaints at admission to re¬ quire the use of antidepressant treatment. Patients under 19 or over 65 years of age, patients with a toxic or neurologic condition, patients whose current manifestations were primarily schizo¬ phrenic, or patients whose depression was a short-lived reaction were excluded. The total sample was divided into three groups: a currently psy¬ chotic group comprising 69 patients, a group comprising 113 pa¬ tients who were neurotic, and a group of 43 patients who were neither psychotic nor neurotic, and, as a consequence, were elimi¬ nated from the present analysis. The diagnostic composition of these three groups is summarized in Table 1. The psychotic group was older and had more previous hospital¬ izations than the neurotic group (Table 2). There was no differ¬ ence in education level.
METHODS The patients were assigned at random to one of the three medi¬ cations (amitriptyline, imipramine, or thioridazine) and were maintained on a double-blind regimen of treatment. No washout period was required before treatment was initiated. The respec¬ tive dosage units were 25 mg, 25 mg, and 50 mg. Six units were recommended as the standard daily dosage, but the regulation of the dosage was managed at the discretion of the psychiatrist. Be¬ cause some patients were severely depressed and treatment re¬ sistant, the recommended daily dosage of six units was frequently exceeded. Since concurrent psychotherapeutic influences may obscure dif¬ ferences in response to various psychotropics, particularly anti¬ depressants and antianxiety medications, the patients in the pres¬ ent inquiry received only enough psychiatric attention to meet the management and assessment requirements of the study. Supple¬ mentary nighttime sedative medication was prescribed for 30% of the sample during the first week of treatment. For the purpose of the present comparison, the short-term use of sedatives in the management of severe initial agitation was considered preferable to psychotherapeutic efforts that could have a persisting effect and
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Table
time the patients started medication therapy and at weekly inter¬ vals thereafter. These three independent ratings were reconciled (by using the most severe rating) on a scale-by-scale basis, and the reconciled set of ratings provided the basis for the data analy¬ sis. The weekly self-report inventories (the Zung self-rating de¬ pression scale and the items from the Minnesota Multiphasic Per¬ sonality Inventory required for the psychasthenia and the depression scores) were prepared by the patients under the psy¬ chologist's supervision. The Zung inventory was scored on the basis of prior factor analyses of the Rutgers-M ari boro data and provided both a positive and a negative mood assessment. A weekly treatment log for each patient included a record of all medication and was used in the present analysis to identify pa¬ tients who had required sedation, who had required more assigned medication than the recommended dosage, and for whom the scheduled treatment was terminated early.
1.—Diagnostic Composition of Sample of 225 Depressed Women
Depressed Psychotic State =
Depressed Neurotic N
69
Psychotic
depressive reaction
113
neurosis
72
depressive
Psychoneurotic
35
depressive
Schizoid
(secondary) Schizophrenic (secondary)
=
Depressive
State not Psychotic nor Neurotic = 43 Involutional 21 Manic-
18
reaction
25
depressed
Alcoholic
(secondary) Depressive
Paranoid
(secondary)
12
Manic-
depressive circular
10
reaction
Depressive
situational
adjustment
Involutional
(secondary)
Alcoholic
(secondary)
RESULTS
during subsequent weeks.
could obscure differences
During the first week of treatment, 56 (30%) of the 182 patients involved in the present comparison received nighttime sedation. Of the 58 persons in the imipramine group, 26 (45%) required sedation, while only 11 (20%) of the 56 persons in the thioridazine group required sedation. This is a statistically significant contrast (P=.05). The need for sedation in the amitriptyline group was inter¬ mediate and did not contrast significantly with the thio¬
Assessments
The long form of the Wittenborn Psychiatric Rating Scales (WPRS) was used as a part of the comprehensive pretreatment assessment of all patients.1 The raw factor scores (based on the average of the ratings for the scales comprising that factor) are relatively sensitive, and small intergroup differences can be statis¬ tically significant. This is illustrated in Table 2, which discloses that in terms of raw factor scores, the psychotic sample was more heavily burdened with symptoms than was the neurotic sample. In order to facilitate intersymptom comparisons, the raw scores can be expressed in terms of standard scores that range from 1 to 10. The standard scores show both samples to be characterized by a relatively high order of anxiety, depression, and obsessive-com¬ pulsive qualities. The WPRS short form symptom ratings were made by the psy¬ chiatrist, the psychologist, and the nurse, independently at the '
ridazine group. Of the 113 neurotic patients, 29 (26%) required night¬ time sedation. Among the 69 psychotic patients, 27 (39%) required nighttime sedation. When the chi-square test was applied, this difference was barely significant at the .05 level and presumably reflects the greater disturbance of the psychotic group. Forty-seven percent of the patients in the psychotic
Table 2.—Pretreatment Contrasts Between
Depressed
Psychotic (N
WPRS Factors*
Anxiety Hysterical conversion Manic state Depressive total Obstructive subscore
Apathy subscore Withdrawal subscore Flatness subscore Schizophrenic excitement
Psychotic belligerence Paranoia
Hebephrenia Compulsive-obsessive Intellectual impairment Homosexual dominance Ideas of grandeur
Demographic data Age,
yr
Educationf Previous Hospitalizations *
Raw Score X 1.20 0.80 0.27 1.12 0.32
=
and Neurotic
Diagnostic Groups Depressed
Neurotic
69) Standard Score
1.33 1.57 0.74 0.38 0.19 0.40
0.35 0.92 0.26 0.23 0.04 X 39.88 3.72 2.33
Wittenborn Psychiatric Rating Scales is indicated by WPRS. was used to compute average education:
t An arbitrary scale pletion of grade 8, 2.
Psychotic
X
(N
=
113)
Raw Score X
Standard Score X
t
1.28 0.72 2.01 3.77 2.31 4.19 2.63 3.41 4.41 0.13 4.82 2.28 2.27 2.94 0.52 0.26
1.10 0.90 0.33 0.84 0.17 0.97 1.25 0.54 0.24 0.19 0.13 0.29 0.76 0.15 0.24 0.04 X 35.43 3.87 1.51
completion of high school indicated by 4;
Raw Score
2.53 0.66 2.47 some
high school, 3; and
com¬
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Table
Mean
3.—Adjusted
Ratings for Week 3 Scores From WPRS Short Form* Treatment Group Means (Raw Score) Adjusted for Pretreatment Differences
WPRS Short Form Score
Anxiety
Depressed
Amitriptyline Hydrochloride
Diagnostic
Imipramine Hydrochloride
X X Neurotic 0.90 0.87 0.73 0.83 Psychotic Combined sample 0.84 0.86 Multifactor Covariance Analysis: = NS Treatment differences = NS Diagnostic differences = NS Diagnosis X treatment interaction Neurotic 0.65 0.64 0.80 0.71 Psychotic Combined sample 0.69 0.69
Grouping
Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction
Obsessive-compulsive
Neurotic
Psychotic
Combined sample
Somatic
0.35 0.52
Diagnostic differences Diagnosis X treatment interaction Paranoia
Neurotic
Psychotic
Combined sample
0.06 0.14 0.08
Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction
Excited
Neurotic
0.27 0.53
Psychotic
Combined sample
0.38 Multifactor Covariance Analysis: differences Treatment Diagnostic differences Diagnosis X treatment interaction
'
Combined Sample X
0.83
0.87 0.86
0.99 0.90
0.82 1.05 0.86
0.69 0.87
0.36 0.45
0.35
0.37 0.47 0.43
NS NS NS 0.40 0.32 0.36
0.48 0.54 0.45
0.45 0.40
0.06 0.05 0.05
0.08 0.10
0.34 0.55 0.42
0.29 0.49
=
= =
NS .07 NS
0.37 0.28
0.41 Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction Neurotic 0.48 0.37 Psychotic Combined sample 0.42 Multifactor Covariance Analysis: Treatment differences
Thioridazine X
=
=
—
NS NS = NS 0.11 =
=
0.12 0.08
=
—
=
NS NS NS
0.29 0.34 0.33 =
=
=
NS .01 NS
Wittenborn Psychiatric Rating Scales indicated by WPRS.
group received more than the recommended dosage dur¬ ing the third week, while only 28% of the neurotic group received more than was recommended. This contrast is statistically significant (P .05) and reflects the treat¬ ment-resistant nature of the symptoms in the psychotic group. In the thioridazine group, more psychotic than neu¬ rotic patients required increased medication, while in the imipramine group more neurotic than psychotic patients required increased medication. About 15% of the 182 patients left the project before the fourth week, but this factor did not distinguish between treatment groups or between diagnostic groups. About 7% of the patients responded to the assigned medication in an unsatisfactory manner and were reassigned to a different medication. This factor did not distinguish among treat¬ ment groups or between diagnostic groups and did not disclose an interaction between diagnosis and treatment. During the successive weeks of treatment, the diminu¬ tion in the various criteria of depression followed a typical decay curve with the greatest drop at the end of the first =
week of treatment and decreasing drops in the various cri¬ terion scores during the successive weeks. This is illus¬ trated in the Figure for the depression score from the WPRS short form; for all treatments, the reduction in se¬ verity was statistically significant by the end of the first week, and no appreciable average reduction occurred after the third week. The covariance analyses summarized in Tables 3 and 4
may be regarded as two-way factorial analyses of week 3 that have been corrected for pretreatment differ¬ ences. The significance of the difference between the cor¬ rected week 3 averages for the medication groups is perti¬ nent to question 1, the significance of the difference between the corrected week 3 averages for the neurotic group and the psychotic group is pertinent to question 2, and the significance of the interaction between treatment scores
(amitriptyline, imipramine, thioridazine) and diagnosis (psychotic vs neurotic) is pertinent to question 3. On the average, the three treatments were equally effi¬ cacious in controlling the present set of depressive mani-
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Table
4.—Adjusted
Mean
Ratings for Week 3 Self-Report Scores* Treatment Group Means (Raw Score) Adjusted for Pretreatment Differences
Self-Report
Criterion Score
MMPI-depression
Amitriptyline
Diagnostic
Hydrochloride
Grouping
X
Neurotic
Psychotic
Combined
MMPI-psychasthenia
sample
Imipramine Hydrochloride X
0.32
0.36
0.39 0.35
0.33 0.37
Multifactor Covariance Analysis:
Treatment differences
=
Diagnostic differences Diagnosis X treatment interaction
=
Neurotic
0.37 0.41
Psychotic
Combined sample
Zung-positive
NS NS 0.41
0.33 0.40
0.38
= = =
2.74
Neurotic
Combined
Sample
X
0.34 0.37
0.40 0.48 0.43
0.39 0.38
2.77
2.71 2.51
NS NS NS
2.65 2.74 2.66 Combined sample 2.74 2.66 Multifactor Covariance Analysis: Treatment differences NS = NS Diagnostic differences = NS Diagnosis X treatment interaction 1.71 Neurotic 1.67 1.76 1.95 Psychotic Combined sample 1.78 1.80 Multifactor Covariance Analysis: = NS Treatment differences = Diagnostic differences .01 = NS Diagnosis X treatment interaction
Psychotic
X 0.35 0.39 0.37
NS
—
Multifactor Covariance Analysis: Treatment differences Diagnostic differences Diagnosis X treatment interaction
Thioridazine
2.22 2.54
—
Zung-negative
1.68 2.05 1.83
1.69 1.86
"Minnesota Multiphasic Personality Inventory indicated by MMPI.
festations in our sample of severely depressed women. With respect to the neurotic-psychotic distinction, the neurotic patients responded better than did the psychotic patients on three criteria: symptoms of depression (P .07), symptoms of excitement (P= .01), and the nega¬ tive self-description of the Zung scale (P .01). The possi¬ bility that the class of drug could be related to diagnostic classification is of great clinical interest. In the present sample, the interactions required to support this possi¬ =
=
bility
were
not
significant.
COMMENT In the 1974
Physicians' Desk Reference,4· thiordazine indicated for patients with neurotic depressive reac¬ tions. Among patients treated with thioridazine, the pres¬ ent results show the depression, the excitement, and the Zung negative scores to be more responsive among neu¬ rotic than among psychotic patients. The indications for amitriptyline and for imipramine in the 1974 Physicians' Desk Reference emphasize endoge¬ nous depressions with no mention of neurotic depressions. The present study did not identify an endogenous group, but the results provide some indications that the neurotic patients, regardless of treatment, respond more advanta¬ geously than the psychotic patients. Certainly, there is no evidence that the assignment of any one of these medica¬ was
tions is disadvantageous for neurotic depressed patients. The relative merit of tricyclic medications and pheno¬ thiazines has provided a topic of persisting interest to clinical psychopharmacologists. Overall et al" described
the general difference between thioridazine and imipra¬ mine as inconsequential. In a later report, Overall et al" examined within-treatment group differences in symptom severity and found that thioridazine was helpful in alle¬ viating the mood in anxious depressions but was not help¬ ful for patients with retarded depressions. In contrast, imipramine improved the mood of retarded patients. Sim¬ ilar contrasts between the tricyclic amitriptyline and the phenothiazine perphenazine were described by Hollister et al7 in a later report. Raskin et al8 examined a neuroticpsychotic distinction in a comparison of chlorpromazine, imipramine, and placebo. In their sample, which was about five years older than the present sample and in¬ cluded both male and female patients, imipramine was judged better than chlorpromazine for the psychotic pa¬ tients and worse for the neurotic patients. A comparison between these findings and the present results suggests that thioridazine might have been a more appropriate an¬ tidepressant than chlorpromazine for depressed neurotic
patients.
The results confirm the hypothesis that in depressed pa¬ tients the phenothiazine tranquilizers (eg, thioridazine) are accompanied by remissive changes similar to those changes that accompany tricyclic antidepressants (eg, amitriptyline and imipramine). The neurotic-psychotic distinction within these treatment groups was not found to qualify this general similarity, and it is proposed that other distinctions" be considered as more promising aids in the selective assignment of these alternative medica¬ tions for depressed patients. The present findings, show-
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¬
Amitriptyline Hydrochloride Ra= mipramine Hydrochloride R ¡=
o
c
o
Thioridazine R t=
«J -
co CD
-*—»
CE CD >
to CD -
.
CD
Q ro
Pretreatment
Week 1
(0
Xa xi
1.51 1.17
1.05
5.5
0.77
4.9
Week 2 0.94 0.86
xt
1.36
0.94
5.0
0.90
2/152
df 2/154 F 2.39
M 2.8
6.6 4.2
5.3
0.84
4.7
6.1
2/149 0.36
0.19
(0
Week 3 0.78 0.66 2/132 0.84
Reduction in average depressive retardation scores from Wittenborn Psychiatric Rat¬ ing Scales (short form) with scores based on mean for three component rating scales; F based on residual scores; and correlated t to show significance of change within groups.
ing that all treatment groups were remitting rapidly, with the psychotic less responsive than the neurotic pa¬ tients correspond with Rockliff's description.10 Rockliff suggests, however, that such improvements as these in a neurotic group may be spontaneous, while those patients in a psychotic group may represent a therapeutic gain. This study was supported by the Psychopharmacology Research Branch, Public Health Service
grant MH 13385,
and
was
conducted
as a
part of
a
program of collaboration between the New Jersey State Hospital at Marl¬ boro and Rutgers Interdisciplinary Research Center. Helen Maurer, MSW, Bette Kiremitci, PhD, Carol Trabalik, RN, and June Rogers, RN, participated in this study.
Nonproprietary Names and Trademarks of Drugs Amitriptyline hydrochloride-.Ë'tomi. Chlorpromazine-Cromedazine, Chlor-pz, Thorazine. Thioridazine—Mellaril.
References 1. Wittenborn JR: Symptom patterns in tients. J Consult Psychol 15:290-302, 1951. 2. Wittenborn JR: The dimensions of
134:117-128, 1962. 3. Wittenborn
a
group of mental
hospital pa-
psychosis. J Nerv
Ment Dis
individual JR, Dempster A, Maurer H, differences as potential predictors of response to pharmacology. J Nerv Ment Dis 139:186-194, 1964. 4. Physicians' Desk Reference, ed 28. Oradell, NJ, Medical Economics Co, 1974. 5. Overall JE, Hollister LE, Meyer F, et al: Imipramine and thioridazine in depressed and schizophrenic patients. JAMA 189:605-608, 1964. et al: Pretreatment
6. Overall JE, Hollister LE, Johnson M, et al: Nosology of depression and differential response to drugs. JAMA 195:946-948, 1966. 7. Hollister LE, Overall JE, Shelton J, et al: Drug therapy of depression. Arch Gen Psychiatry 17:486-493, 1967. 8. Raskin A, Schutterbrandt JG, Reatig N, et al: Differential response to chlorpromazine, imipramine, and placebo. Arch Gen Psychiatry 23:164-173, 1970. 9. Wittenborn JR, Kiremitci N, Weber ESP: The choice of alternative antidepressants. J Nerv Ment Dis 156:97-108, 1973. 10. Rockliff BW: Measurement of drug effects in newly hospitalized depressives. Dis Nerv Syst 32:532-537, 1971.
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